17-43106477-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_StrongPM2_SupportingPP3PS3

This summary comes from the ClinGen Evidence Repository: The c.191G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 64 (p.Cys64Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.557, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 17239845573264 (based on Cosegregation LR=5300394; Pathology LR=189; Family History LR=17201), above the threshold for Very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMID:31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA001262/MONDO:0011450/092

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_001407853.1 splice_donor, intron

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:26O:1

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.191G>A	p.Cys64Tyr	missense_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.191G>A	p.Cys64Tyr	missense_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721804

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:9Other:1

May 28, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The pathogenic BRCA1 Cys64Tyr was detected in this specimen. This sequence change replaces cysteine with tyrosine at codon 64 of the BRCA1 protein (p.Cys64Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary breast and ovarian cancer in two families (PMID: 15131401), and has been observed in numerous individuals with breast and/or ovarian cancer (PMID: 22034289, 23397983, 18489799, 19949876, 25085752). ClinVar contains an entry for this variant (Variation ID: 54400). Experimental studies have shown that this missense change abolishes E3 ubiquitin ligase activity (PMID: 11320250). This missense change is located at a functionally conserved residue within the RING domain of the BRCA1 protein (PMID: 8944023, 11526114), and a significant number of previously reported BRCA1 missense mutations have been found at this residue (PMID: 7894491, 19287957, 24516540, 23161852). Based on multifactorial likelihood algorithms using individuals' personal and family history of cancer, this variant has been determined to have a high probability of being pathogenic (PMID: 25085752, 18418466). Therefore, this variant has been classified as Pathogenic . -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PS3; PS4; PM2; PP3; PP5 -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

not provided

Pathogenic:8

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 23397983 (2014), 22034289 (2012), 19949876 (2010), 18489799 (2008), 15131401 (2004), 8807330 (1996)). Multiple functional studies have demonstrated that this variant has a damaging effect on BRCA1 protein function (PMID: 30209399 (2018), 27272900 (2016), 25823446 (2015), 23397983 (2014), 22034289 (2012), 15131401 (2004), 8944023 (1996)). Based on the available information, this variant is classified as pathogenic. -

Jun 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in numerous Hereditary Breast and Ovarian Cancer families (Taylor 1998, Laplace-Marieze 1999, Shih 2000, Krajc 2008, Stegel 2011, Zhang 2012, Novakovic 2012, Krajc 2014, Cvelbar 2017); Published functional studies demonstrate a damaging effect: reduced or absent ubiquitin ligase activity, decreased BARD1 binding, decreased cell survival, and abnormal yeast colony size and spot formation (Ruffner 2001, Starita 2015, Thouvenot 2016, Findlay 2018); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 310G>A; This variant is associated with the following publications: (PMID: 25451870, 31467430, 15235020, 8807330, 18783588, 11927492, 23397983, 9699523, 22739995, 23192404, 21232165, 18489799, 11106241, 11320250, 22505045, 22923021, 8944023, 25823446, 27272900, 22753008, 15131401, 9808526, 10200350, 25085752, 29446198, 30696104, 31131967, 28740454, 31209999, 25525159, 32341426, 30787465, 30209399, 32741062, 33087888, 19949876, 22034289, 11526114, 7894491, 23161852, 24516540, 19287957, 36171877, 35464868, 35659930, 34930662, 24389207, 20104584, 28888541, 30322717, 33758026, 30130155) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4_very_strong, PM2, PS3 -

Hereditary breast ovarian cancer syndrome

Pathogenic:5

Mar 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.191G>A (p.Cys64Tyr) results in a non-conservative amino acid change located in the RING domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250804 control chromosomes. c.191G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in a loss of homology directed repair (HDR) activity. Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=9 including the expert panel)/likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 64 of the BRCA1 protein (p.Cys64Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer and breast and/or ovarian cancer (PMID: 15131401, 18489799, 19949876, 22034289, 23397983, 25085752). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54400). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 7894491, 8944023, 11320250, 11526114, 19287957, 23161852, 24516540). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8944023, 11526114). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 08, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). , PM2 (supporting pathogenic): Absent from controls , PP3 (supporting pathogenic): inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28), PP4 (very strong pathogenic): Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 17239845573264 (based on Cosegregation LR=5300394; Pathology LR=189; Family History LR=17201), above the threshold for Very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMID: 31131967, 31853058). -

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Sep 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C64Y pathogenic mutation (also known as c.191G>A), located in coding exon 3 of the BRCA1 gene, results from a G to A substitution at nucleotide position 191. The cysteine at codon 64 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C64Y mutation has been detected in multiple families with hereditary breast and ovarian cancer (Shih H et al. Clin Cancer Res. 2000;6:4259-4264; Machackova E et al. BMC Cancer 2008;8:140; Stegel V et al. BMC Med. Genet. 2011;12:9; Zhang J et al. Breast Cancer Res. Treat. 2012 Jul;134(2):889-94; Krajc M et al. Clin. Genet. 2014 Jan; 85(1):59-63; Cvelbar M et al. Radiol Oncol. 2017 Jun;51:187-194; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488). This alteration is located in the highly conserved 5' RING domain and has been shown to result in abolished ubiquitin protein ligase activity (Ruffner H et al.Proc Natl Acad Sci USA. 2001 Apr 24;98(9):5134-9). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Additionally, another alteration impacting this codon, p.C64G, has been reported as pathogenic (Caleca L et al. PLoS One. 2014 Mar;9:e86924). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jun 01, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 64 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in ubiquitin ligase, BARD1 binding, haploid cell proliferation and yeast colony size assays (PMID: 11320250, 12732733, 25823446, 27272900, 30209399). This variant has been reported in over 10 individuals affected with breast and ovarian cancer (PMID: 9699523, 11015464, 14760071, 15131401, 22034289, 23192404) and in suspected hereditary breast and ovarian cancer families (PMID:18489799, 19949876, 23397983). This variant also has been reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 5300394 and 189, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

BRCA1-related cancer predisposition

Pathogenic:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.191G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 64 (p.Cys64Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.557, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 17239845573264 (based on Cosegregation LR=5300394; Pathology LR=189; Family History LR=17201), above the threshold for Very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Very strong). -

Pancreatic cancer, susceptibility to, 4

Pathogenic:1

Aug 18, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant:PS3, PS4, PM5, PM2_SUP, PP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

.;T;.;.;.;.;D;.;.;T;T;D;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.3

H;H;H;H;.;H;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

N;N;N;D;N;N;D;N;N;.;N;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;.;D;D;D;.

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;.;D;D;.;D;D;.;.

Polyphen

1.0, 1.0

.;D;.;.;.;D;.;.;D;.;.;.;.;.

Vest4

0.95

MutPred

0.99

Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);.;Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);.;Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);.;

MVP

1.0

MPC

0.56

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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