Submissions for variant NM_007294.4(BRCA1):c.190T>C (p.Cys64Arg)

dbSNP: rs80357064

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130787	SCV000185680	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	The p.C64R pathogenic mutation (also known as c.190T>C), located in coding exon 3 of the BRCA1 gene, results from a T to C substitution at nucleotide position 190. The cysteine at codon 64 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation is located in the highly conserved RING-finger motif of BRCA1, has been observed to segregate with disease in multiple breast and ovarian cancer families, and has been described as an Italian founder mutation (Jakubowska A et al. Hum. Mutat. 2001;18:149–156; Willems P et al. Int J Oncol. 2009;34(4):1005-15; Marchina E et al. Oncol Rep. 2010;24(6):1661-7; Caleca L et al. PLoS ONE, 2014 Feb;9:e86924). 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). In addition, other functional studies have shown that p.C64R adversely affects the BRCA1/BARD1 complex formation, and leads to increased sensitivity to ionizing radiation and chromosomal instability (Caleca L et al. PLoS ONE, 2014 Feb;9:e86924; Cochran RL et al. Oncotarget, 2015 Sep;6:25240-51). Of note, this alteration is also referred to as 309T>C 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083174	SCV000325176	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130787	SCV000688353	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine 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). This variant alters a conserved cysteine in the RING domain and functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, BARD1 binding, ubiquitin E3 ligase, a haploid cell proliferation, sensitivity to ionizing radiation and PARP inhibitors and chromosomal instability assays (PMID: 24516540, 25823446, 26246475, 28398198, 30209399). This variant has been reported in over 90 individuals affected with breast and ovarian cancer and in suspected hereditary breast and ovarian cancer families in Europe, Asia and South America (PMID: 8875986, 11462239, 14531499, 16140926, 19287957, 24516540, 24249303, 27741520, 28993434, 30103829, 30702160, 30972954, 34906479). Haplotype analysis indicates that this variant is a founder mutation in Italy (PMID: 24516540). This variant has been reported to confer lower risk for breast cancer and high risk for ovarian cancer compared to other pathogenic BRCA1 variants (PMID: 34906479). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000083174	SCV001251425	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195433	SCV001365790	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-10	criteria provided, single submitter	clinical testing	The p.Cys64Arg variant in BRCA1 has been identified in >50 pan-ethnic individuals with BRCA1-associated cancers and segregated with disease in at least 15 individuals from several families (Caligo 1996, Willems 2009, Marchina 2010, Caleca 2014, Shi 2017, Park 2017, Rebbeck 2018, Cardoso 2018, Palmero 2018, Wen 2018, Li 2019, Deng 2019, Bhaskaran 2019, Breast Cancer Information Core (BIC; https://research.nhgri.nih.gov/bic/). This variant has been described as a founder variant in the Italian population (Caleca 2014). In addition, it has also been reported by other clinical laboratories in ClinVar (Variation ID 54394) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, and in vitro functional studies support an impact on protein function (Willems 2009, Caleca 2014, Cochran 2015, Findlay 2018). Another variant involving this codon (p.Cys64Gly) has been identified in individuals with hereditary breast and ovarian cancer (HBOC) and is currently classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PM5, PS3_Supporting, PP1_Strong, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284284	SCV001469985	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing	This variant has been reported as a founder mutation in hereditary breast/ovarian cancer (HBOC) families in the Italian population (PMID: 24516540 (2014), 19287957 (2009)) and has also been observed in multiple other individuals/families of various ethnicities with HBOC (PMID: 29752822 (2018), 29446198 (2018), 28111427 (2017)). Functional studies indicated that this variant has a damaging effect on the function of the protein (PMID: 24516540 (2014), 26246475 (2015), 25823446 (2015)). Based on the available information, this variant is classified as pathogenic.
Invitae	RCV001195433	SCV001582761	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-07	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. 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: 9042907, 12732733, 16140926, 20103620, 23161852, 23867111, 26689913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 24516540; Invitae). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 19287957, 24516540, 25823446). ClinVar contains an entry for this variant (Variation ID: 54394). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 8875986, 11462239, 14531499, 21042765, 24249303, 24516540, 27741520). It is commonly reported in individuals of Italian ancestry (PMID: 8875986, 11462239, 14531499, 21042765, 24249303, 24516540, 27741520). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 64 of the BRCA1 protein (p.Cys64Arg).
Mendelics	RCV002247441	SCV002518595	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001284284	SCV003809857	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000083174	SCV004216865	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083174	SCV000115248	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083174	SCV000144596	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	RCV000496744	SCV000587027	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000083174	SCV001241646	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Laboratory for Genotyping Development, RIKEN	RCV003162401	SCV002758213	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000083174	SCV004244185	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing