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

dbSNP: rs80356914

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049030	SCV000077043	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-28	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 37680). Invitae Evidence Modeling incorporating data from in vitro 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: 20516115, 27802165, 30209399). 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. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000774925	SCV000908977	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 1837 in the BRCT2 domain of the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant may cause defects in protease sensitivity, peptide binding, transcription activation and reduce homology directed repair activity (PMID: 20516115, 27802165, Ambry's ACMG 2018 poster). Additionally, this variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in 1 individual affected with ovarian cancer (PMID: 31124283). Different missense substitutions at the same codon p.Trp1837Arg and p.Trp1837Gly have been reported to be likely pathogenic in Clinvar (Variant ID: 37679, 55607), which suggests that the tryptophan residue is critical for BRCA1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049030	SCV000916815	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5511G>T (p.Trp1837Cys) results in a non-conservative amino acid change located in the C-terminal BRCT domain (Ghani-Kakhki_2012) 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 246126 control chromosomes (gnomAD). c.5511G>T has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. Although, the variant, c.5511G>C, that causes the same missense change has been reported in a BrC patient as a somatic occurrence (Li_2016). Multiple functional studies have been performed on this variant and found it to significantly impact transcriptional activity, binding ability and protein folding (Carvalho_2014, Lee_2010, Thouvenot_2016). In addition, other missense changes affecting this codon, Trp1837Arg and Trp1837Gly, have been reported in affected individuals suggesting a mutational hotspot. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV000774925	SCV001186187	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-07	criteria provided, single submitter	clinical testing	The p.W1837C pathogenic mutation (also known as c.5511G>T), located in coding exon 22 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5511. The tryptophan at codon 1837 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the BRCT domain and has been found to impair nuclear localization, transcriptional activation, and in vivo protein folding (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Thouvenot P et al. J. Cell. Sci., 2016 12;129:4366-4378). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Several other missense variants at the same codon, including p.W1837R and p.W1837G, have also been shown to be structurally and functionally deficient. 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 variant is interpreted as a disease-causing mutation.
GeneDx	RCV005055528	SCV005689899	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased cell survival, protein misfolding, aberrant cellular localization, compromised DNA binding and transactivation, and impaired homology-directed repair activity (PMID: 20516115, 27802165, 30209399, 35665744); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5630G>T; This variant is associated with the following publications: (PMID: 24845084, 32042831, 30209399, 27802165, 20516115, 26956035, 35665744, 27741520, 28324225, 22855649, 15689452, 11802209, 8968102, 25348405, 34981296, 32377563, 33649982, 35070997, 38355628, 32803532, 31853058)
Sharing Clinical Reports Project (SCRP)	RCV000031261	SCV000053865	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031261	SCV000145562	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031261	SCV001244042	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro