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Workshop ACMG-AMP classification
laner@mgz-muenchen.de benet-pages@mgz-muenchen.de
ACMG-AMP criteria and data sources
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
?Are these papers really valid
lines of evidence
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Not consistent
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
Case 1Case 1 PATIENT: Male, 46 years of age.
PHENOTYPE: Mental retardation, hypophosphatemia and spinal deformity (osteopenia). Family
history negative regarding mental retardation or skeletal abnormalities.
HPO-TERMS: Hypophosphatemia, Osteopenia
ANALYSED GENES: Clinical Exome-Kit (Illumina; 3.963 genes)
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC9A3R1 NM_004252.4 c.328C>G
(p.Leu110Val) heterozygous C G chr17:72745313 rs35910969
BS1+BS2 Class 1 – benign
Carefully interpret Literature and Database entries
It is not surprising to find a “common variant” in your patient (with a “common” phenotype)
?
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2: PATIENT: Female, 38 years of age.
PHENOTYPE: Breast-cancer, mother and maternal aunt also affected by breast-cancer at age 45
and 59, respectively. Clinical suspicion of hereditary breast-cancer. No family
segregation analysis performed.
ANALYSED GENES: 12
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
CHEK2 NM_007194.3 c.470T>C
(p.Ile157Thr) heterozygous A G chr22:29121087 rs17879961
Case 2
Valid lines of conflicting evidence
ACMG-AMP system is intended for “high penetrant” mendeliangenes
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Maybe a new class will/ should be established:
“Pathogenic –low penetrance”
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Not consistent
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
HGMD
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
HGMD
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
HGMD
Case 3PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
PATIENT: Male, 2 years of age.
PHENOTYPE: Childhood cardiomyopathy, poor feeding, and muscle hypotonia.
ANALYSED GENES: 23
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
SLC22A5 NM_003060.3 c.1463G>A
(p.Arg488His) homozygous G A chr5:131729380
rs28383481
BS1+BS2Class 1 –benign
ACMG-AMP for “single” variants in mendeliangenes(not digenic, not haplotypes, not trans-genomic-contextual variants)
?
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
No information
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
Alteration of Glycinin “Collagen triple helix repeat” domain
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Expert Opinion:
Move „PM1“ to
„Strong“
1 Strong + PM2+ PP3 = Class 4
Otherwise: PM1 + PM2 +PP3 = Class 3 VUS
Biology: virtually all described
pathogenic variants in COL4A1
(and COL4A2) alter Glycin
residues in the „Collagen“
domain of the protein
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Case 4
No information
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
When a variant is observed in a case with a clear alternate
genetic cause of disease, this is generally considered
supporting evidence to classify the variant as benign.
Case 4
BP4+BP5 = class 2
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
benign
Case 4
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696
-
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268
rs778978790
PATIENT: Male, 30 years of age
PHENOTYPE: Intracerebral hemorrhage at age 27. Positive family history of porencephaly, father
deceased of haemorrhagic stroke.
ANALYSED GENES: 22
DETECTED VARIANT(S):
Gene
(GRCh37/hg19)
Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
COL4A1 NM_001845.5 c.3067G>A
(p.Gly1023Arg)
heterozygous C T chr13:110827696 -
COL4A1 NM_001845.5 c.3484G>A
(p.Ala1162Thr)
heterozygous C T chr13:110826268 rs778978790
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
For certain genes / diseases with a special “biology” expert knowledge helps for proper interpretation(COLx-genes; NOTCH3 (Cys); RB1; Muscle genes, …)
Don’t hesitate to consult an expert (e.g. LSDB curators, scientific meetings, literature, private “network”)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PS3+PM2+PM5+PP1+PP3 = class 5
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Described in several patients with
recessive FHD in compound
heterozygous state with LOF variants
Segregates with disease (FHD)6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303
7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258
8. Pollard (2005) Hum Mol Genet. 14: 2231 PubMed: 15987702
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Functional studies demonstrate that
a compound heterozygous state of
c.1431_1433dup with LOF variant
cause a significant reduction of FH
activity
Phenotype (FHD) is highly specific
for LOF in the FH gene
6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303
7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258
8. Pollard (2005) Hum Mol Genet. 14: 2231 PubMed: 15987702
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Found in patients with RCC and/ or
Leiomyoma as well as in controls
6. Deschauer (2006) Mol Genet Metab. 88: 146 PubMed: 16510303
7. Ezgu (2013) Gene. 25: 403 PubMed: 23612258
8. Pollard (2005) Hum Mol Genet. 14: 2231 PubMed: 15987702
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Protein length change (in-frame
indel) in a non-repeat region
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Summary of ACMG-AMP criteria:
• PS3: functional study shows FD (FHD and HLRCC)• PM3: detected in trans with pathogenic for recessive disease (FHD)• PM4: protein length change in non-repeat region (FHD and HLRCC)• PP1: co-segregation with disease (FHD)• PP4: phenotype is highly specific (FHD) • BS1: allele frequency greater than expected (FHD and HLRCC)• BS2: observed in healthy adult homoz. (for AR, eaerly onset) (FHD)
PS3 + PM3 + PM4 + PP1 + PP4 (BS1/BS2) = class 5 for FHD
PS3 + PM4 (BS1) = class 4 (reduced penetrance) for HLRCC
• Valid but conflicting lines of evidence
• Reduced / Low penetrance
• Two loss-of-function variants would be lethal (complete FHD)
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Case 5PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
PATIENT: Female, 46 years of age.
PHENOTYPE: Astrocytoma at 10 years of age, breast
cancer at 29 years of age, colorectal cancer
at 39 years of age, kidney cancer at 45 years
of age. Microsatellite stable with expression
of all mismatch repair genes.
ANALYSED GENES: 94
DETECTED VARIANT(S):
Gene
(GRCh37/hg19) Transcript Variant (HGVS) Zygosity Ref Alt Chr. Position dbSNP ID
TP53 NM_000546.5 c.722C>T
(p.Ser241Phe) heterozygous G A chr17:7577559 rs28934573
FH NM_000143.3 c.1431_1433dup
(p.Lys477dup) heterozygous - TTT chr1:241661227-241661228 rs367543046
Population DB´s(ExAC, gnomAD, 1000G,
ESP, dbSNP…)
Internal Data(segregation, functional
studies)
Literature(PubMed, HGMD,
Google scholar)
LSDB´s(LOVD, ClinVar, UMD)
Prediction Tools(see ACMG/AMP)
Pathogenic, but with reduced penetrance
Relevant Phenotype:
• (Kidney) Cancer, not FH-Deficiency
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