ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.190T>C (p.Cys64Arg) (rs80357064)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130787 SCV000185680 pathogenic Hereditary cancer-predisposing syndrome 2019-03-16 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). In addition, 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). This alteration is also referred to as 309T>C in published literature. 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 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130787 SCV000688353 pathogenic Hereditary cancer-predisposing syndrome 2020-11-10 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). Experimental functional studies of this variant have demonstrated decreased homologous recombination activity, increased sensitivity to PARP inhibitors and ionizing radiation, increased chromosomal instability and centrosome amplification, and loss of BARD1 interaction consistent with the expected impact on zinc ion coordination and stability of the BRCA1 RING domain (PMID: 28398198, 26246475, 24516540, 12732733). This variant has been reported in numerous individuals affected with hereditary breast and/or ovarian cancer in the literature (PMID 10788334, 24516540) and has been shown to segregate with disease in multiple families of Northern Italian descent (PMID: 24516540). 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 1 2019-10-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195433 SCV001365790 pathogenic Hereditary breast and 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 Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV001195433 SCV001582761 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 64 of the BRCA1 protein (p.Cys64Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (rs80357064, ExAC no frequency). This variant has been reported in the literature in individuals affected with breast cancer or with a family history of breast and ovarian cancer (PMID: 8875986, 24516540, 21042765, 11462239, 24249303, 14531499, 27741520), and has been proposed to be a founder mutation in the Italian population (PMID: 24516540). ClinVar contains an entry for this variant (Variation ID: 54394). This variant affects the highly conserved Cys64 residue within the N-terminal RING domain of the BRCA1 protein, which is important for the interaction between BRCA1 and BARD1 (PMID: 22843421, 16633366). Experimental studies have shown that this variant disrupts BRCA1-BARD1 complex formation, which results in the loss of the BARD1-mediated E3 ubiquitin ligase activity of BRCA1 and affects the homology-directed repair, and tumor suppressor functions of BRCA1 (PMID: 24516540, 19287957, 25823446). A different missense substitutions at this codon (p.Cys64Gly) has been determined to be pathogenic (PMID: 20103620, 23161852, 23867111, 12732733, 26689913, 9042907, 16140926). This also suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000083174 SCV000115248 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083174 SCV000144596 uncertain significance Breast-ovarian cancer, familial 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 1 no assertion provided in vitro

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