ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.115T>A (p.Cys39Ser) (rs80357164)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509615 SCV000608086 pathogenic Hereditary cancer-predisposing syndrome 2020-08-06 criteria provided, single submitter clinical testing The p.C39S pathogenic mutation (also known as c.115T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 115. The cysteine at codon 39 is replaced by serine, an amino acid with dissimilar properties. The p.C39S alteration is located in a critical region of the BRCA1 protein RING domain. A functional study has shown that changes at this residue alter the structure of the RING domain and negatively impact ubiquitin-ligase activity and BARD1 binding activity (Starita LM et al. Genetics. 2015 Jun;200(2):413-22). This alteration was also shown to be non-functional in a high throughput genome editing haploid cell survival assay (Findlay G et al. Nature 2018 10;562(7726):217-222). The p.C39S variant has been reported in breast and/or ovarian cancer families from Spain. (Blay P et al. BMC Cancer 2013;13:243; Rebbeck T et al. Hum. Mutat. 2018 05;39(5):593-620). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759489 SCV000888834 pathogenic not provided 2019-12-12 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. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781001 SCV000918746 pathogenic Hereditary breast and ovarian cancer syndrome 2019-09-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.115T>A (p.Cys39Ser) results in a non-conservative amino acid change located in the Zinc finger, C3HC4 RING-type domain (IPR018957) 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 251086 control chromosomes (gnomAD). c.115T>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Beristain_2007, Sweet_2010, Blay_2013, Mgbemena_2017, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Starita_2015). Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000509615 SCV001351373 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-23 criteria provided, single submitter clinical testing This missense variant replaces cysteine with serine at codon 39 in the RING domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Multiple functional studies have shown that this variant causes a reduction in BARD1 binding and/or ubiquitin-ligase activity (PMID: 12732733, 16403807, 25823446). This variant has been shown to cause loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 17262179; Color internal data) and in an individual affected with ovarian cancer (PMID: 28122244). 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 Likely Pathogenic.
Invitae RCV000781001 SCV001579181 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 39 of the BRCA1 protein (p.Cys39Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (rs80357164, ExAC no frequency). This variant has been reported in two families affected with breast and ovarian cancer (PMID: 17262179, 23683081). This variant is also known as 234T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 54151). This variant affects the highly conserved Cys39 residue within the second Zn2+ binding loop of the N-terminal BRCA1 RING domain (PMID: 12732733, 22843421). Experimental studies have shown that this missense change alters the ability of BRCA1 to complex with BARD1, and abrogates their ubiquitin ligase activity (PMID: 16403807, 25823446). Different missense substitutions at this codon (p.Cys39Arg, p.Cys39Tyr, Cys39Gly) have been determined to be pathogenic (PMID: 9808526, 11320250, 12827452, 19543972, 21725363, 21922593, 21990134, 17319787, 18500671). This 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111803 SCV000144348 uncertain significance Breast-ovarian cancer, familial 1 1998-03-04 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111803 SCV001241899 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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