Submissions for variant NM_007294.4(BRCA1):c.191G>A (p.Cys64Tyr)

dbSNP: rs55851803

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566890	SCV004101417	pathogenic	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047641	SCV000075654	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-30	criteria provided, single submitter	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.
Ambry Genetics	RCV000131896	SCV000186951	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-09	criteria provided, single submitter	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.
GeneDx	RCV000236464	SCV000292502	pathogenic	not provided	2023-06-28	criteria provided, single submitter	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)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077501	SCV000325182	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236464	SCV000600273	pathogenic	not provided	2020-09-26	criteria provided, single submitter	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.
Counsyl	RCV000077501	SCV000677635	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131896	SCV000911053	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047641	SCV000918679	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-28	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV000236464	SCV001249216	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000077501	SCV001439390	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-02-28	criteria provided, single submitter	research	ACMG codes:PS3; PS4; PM2; PP3; PP5
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000077501	SCV001499630	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047641	SCV002505010	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236464	SCV003818016	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236464	SCV004026825	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003334380	SCV004042798	pathogenic	Pancreatic cancer, susceptibility to, 4	2023-08-18	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PS3, PS4, PM5, PM2_SUP, PP1
Baylor Genetics	RCV000077501	SCV004212774	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000236464	SCV004224949	pathogenic	not provided	2024-04-19	criteria provided, single submitter	clinical testing	PP4_very_strong, PM2, PS3
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000047641	SCV005374666	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-08	criteria provided, single submitter	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).
Sharing Clinical Reports Project (SCRP)	RCV000077501	SCV000109301	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-05-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077501	SCV000144599	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047641	SCV000587029	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077501	SCV000733678	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077501	SCV001242528	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236464	SCV001959431	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000236464	SCV001968693	pathogenic	not provided		no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077501	SCV003927164	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	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 .