Submissions for variant NM_007294.4(BRCA1):c.5511G>C (p.Trp1837Cys)

dbSNP: rs80356914

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483084	SCV000570380	pathogenic	not provided	2020-02-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5630G>C; This variant is associated with the following publications: (PMID: 26956035, 22855649, 20516115, 24845084, 30209399, 28781887, 29752822, 30765603, 31124283, 31825140)
Color Diagnostics, LLC DBA Color Health	RCV001184314	SCV001350265	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 1837 in the BRCT2 domain 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 shown that this variant has reduced HDR activity, (Ambry data: https://www.ambrygen.com/science/scientific-poster/197/) exhibits severe defects in protease sensitivity, phosphopeptide binding, transcriptional activation, and has been reported to be a loss of function mutation in a haploid cell proliferation assay (PMID: 20516115, 30209399). Functional studies in yeast have shown that this variant exhibits subcellular mislocalization to the cytoplasm, reduced protein stability and a reduced ability to inhibit cell growth (PMID: 27802165). This variant has been reported in individuals affected with ovarian cancer (PMID: 31124283) and breast cancer (Lertwilaiwittaya et al. 2020, https://doi.org/10.21203/rs.3.rs-122156/v1; Color internal data). This variant has also been observed in an individual affected with breast and ovarian cancer, with early-onset breast cancer and ovarian cancer in her two sisters (PMID: 32803532). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense variants occurring at the same amino acid position, p.Trp1837Ser/Cys/Arg/Gly, are reported to be disease-causing, indicating that tryptophan at this position is important for BRCA1 function (ClinVar variation ID: 1065962, 421244, 37680, 853483, 55607). Based on the available evidence, this variant is classified as Pathogenic.
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV001254336	SCV001430321	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001254336	SCV002109539	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp1837 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8968102, 11802209, 15689452, 27741520, 28324225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 27802165, 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 421244). This missense change has been observed in individual(s) with hereditary breast cancer and/or ovarian cancer (PMID: 29752822; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1837 of the BRCA1 protein (p.Trp1837Cys).
Ambry Genetics	RCV001184314	SCV003856601	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-29	criteria provided, single submitter	clinical testing	The p.W1837C pathogenic mutation (also known as c.5511G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5511. The tryptophan at codon 1837 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in multiple breast cancer patients (Li JY et al. Int J Cancer. 2019 Jan;144:281-289; Wan Q et al. Fam Cancer. 2021 Apr;20:85-95). Multiple functional analyses have found that this nucleotide substitution to leads to a non-functional protein (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Findlay GM et al. Nature. 2018 Oct;562:217-222; Wan Q et al. Fam Cancer. 2021 Apr;20:85-95). 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.
Brotman Baty Institute, University of Washington	RCV001078019	SCV001244041	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro