Submissions for variant NM_007294.4(BRCA1):c.190T>G (p.Cys64Gly)

gnomAD frequency: 0.00001  dbSNP: rs80357064

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047634	SCV000075647	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 64 of the BRCA1 protein (p.Cys64Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357064, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 7894491, 9042907, 26689913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17660). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 20103620, 23161852). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12915465, 26689913; Invitae). 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: 11320250, 18489799, 22034289, 24516540). 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	RCV000129894	SCV000184711	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The p.C64G pathogenic mutation (also known as c.190T>G), located in coding exon 3 of the BRCA1 gene, results from a T to G substitution at nucleotide position 190. The cysteine at codon 64 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation was first described in an African American kindred with multiple cases of early-onset breast and ovarian cancer and segregated with disease (Castilla LH et al. Nat Genet. 1994 Dec;8:387-91). This mutation has also been identified in multiple hereditary breast and ovarian cancer (HBOC) families (Merajver SD et al. Clin Cancer Res, 1995 May;1:539-44; Serova OM et al. Am J Hum Genet, 1997 Mar;60:486-95; Shih HA et al. Clin Cancer Res, 2000 Nov;6:4259-64; Sinilnikova OM et al. Fam Cancer, 2006;5:15-20; Churpek JE et al. Breast Cancer Res Treat, 2015 Jan;149:31-9; Tung N et al. Cancer, 2015 Jan;121:25-33; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-6200), as well as in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). in silico studies predict that this alteration will simultaneously disrupt a putative exonic splicing enhancer motif and activate a cryptic 5' splice site in coding exon 4 (Willems P et al. Int. J. Oncol. 2009 Apr;34:1005-15; Mucaki EJ et al. Hum. Mutat. 2011 Jul;32:735-42). This results in a 22-nucleotide partial exon skipping event which is predicted to lead to a truncated protein consisting of only 63 amino acids (Ambry internal data; Yang Y et al. Hum. Mol. Genet 2003 Sep;12:2121-31). Additionally, this alteration has been classified as deleterious by an alternative functional mechanism resulting from disruption of a zinc-binding ring finger residue at this position. Several independent DNA repair assays showed loss of function in p.C64G point mutants for BRCA1 ubiquitin ligase activity, homology directed recombination, functional complementation, and a high-throughput, genome editing, haploid cell survival assay (Scully R et al. Mol Cell, 1999 Dec;4:1093-9; Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lu C et al. Nat Commun 2015 Dec;6:10086; Starita LM et al. Genetics. 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 10;562:217-222). This alteration is also referred to as 309T>G in published literature. 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 available evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000235121	SCV000210068	pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective homologous recombination and single-strand annealing repair, impaired BARD1 binding, and abrogation of ubiquitin ligase activity (Wu et al., 1996; Brzovic et al., 2003; Ransburgh et al., 2010; Bouwman et al., 2013; Towler et al., 2013; Lu et al., 2015); Observed in individuals with familial breast and/or ovarian cancer (Castilla et al., 1994; Churpek et al., 2015; Lynce et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 309T>G; This variant is associated with the following publications: (PMID: 23867111, 7894491, 23161852, 20103620, 25428789, 26689913, 26295337, 29922827, 26250392, 8944023, 12732733, 12915465, 12438698, 9167459, 27977889, 25823446, 28831036, 30209399, 30696104, 25186627, 24516540, 22034289, 18489799, 16140926, 11927492, 11320250, 11106241, 29446198, 25525159, 33087888, 30787465, 32832836, 30736435, 24389207, 20104584)
Counsyl	RCV000019228	SCV000221114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-04	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019228	SCV000325177	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047634	SCV000698899	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.190T>G (p.Cys64Gly) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Yang_2003). The variant allele was found at a frequency of 1.2e-05 in 251096 control chromosomes. This variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Castilla_1994, Lynce_2015, Tung_2015, Shih_2000, Serova_1997, Palmer_2020). These data indicate that the variant is very likely to be associated with disease. Functional studies using HeLa cells confirmed this variant to be deleterious by using homology-directed recombination (HDR) and single-strand annealing (SSA) assays (Ransburgh_2010, Towler_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235121	SCV000888856	pathogenic	not provided	2020-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129894	SCV000905209	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine 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). RNA study has observed that this variant causes an increase in cryptic out-of-frame splicing in exon 4 (PMID: 12915465) and functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399). This variant has been detected in at least 7 individuals and families affected with breast and ovarian cancers, and this variant was found to segregate with disease in a large pedigree with a LOD score of 2.74 (PMID: 7894491, 9042907, 9816013, 25428789, 26250392, 26689913, 28831036). This variant has been identified in 3/250804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV000019228	SCV004215173	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000019228	SCV004823687	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine 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). RNA study has observed that this variant causes an increase in cryptic out-of-frame splicing in exon 4 (PMID: 12915465) and functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399). This variant has been detected in at least 7 individuals and families affected with breast and ovarian cancers, and this variant was found to segregate with disease in a large pedigree with a LOD score of 2.74 (PMID: 7894491, 9042907, 9816013, 25428789, 26250392, 26689913, 28831036). This variant has been identified in 3/250804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047634	SCV004847796	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The p.Cys64Gly variant in BRCA1 has been identified in at least 13 individuals with BRCA1-associated cancers and segregated with disease in at least 6 individuals from 2 families (Thompson 2002, Lynce 2015, Lu 2015, Serova 1997, Rebbeck 2018, Castilla 1994, Maxwell 2017). In addition, this variant has also been reported in ClinVar (Variation ID 17660). This variant has also been identified in 3/16182 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Findlay 2018, Wu 1996, Ruffner 2001, Yang 2003, Bouwman 2013, Towler 2013, Morris 2006, Lu 2015, Castilla 1994, Ransburgh 2010, Starita 2015, Maxwell 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1_Moderate, PP3
OMIM	RCV000019228	SCV000039516	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019228	SCV000109300	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-06-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019228	SCV000144597	uncertain significance	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	RCV000496255	SCV000587028	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000019228	SCV001241647	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro