Submissions for variant NM_007294.4(BRCA1):c.5511G>T (p.Trp1837Cys) (rs80356914)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049030	SCV000077043	pathogenic	Hereditary breast and ovarian cancer syndrome	2020-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan with cysteine at codon 1837 of the BRCA1 protein (p.Trp1837Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 37680). This variant has been reported to affect BRCA1 protein 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 observed in individuals with BRCA1-related conditions (PMID: 28324225, 11802209, 27741520, 8968102, 15689452), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc	RCV000774925	SCV000908977	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049030	SCV000916815	likely pathogenic	Hereditary breast and 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	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-10-17	criteria provided, single submitter	clinical testing	The p.W1837C variant (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). Several other missense alterations, 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 majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031261	SCV000053865	uncertain significance	Breast-ovarian cancer, familial 1	2010-09-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031261	SCV000145562	uncertain significance	Breast-ovarian cancer, familial 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute,University of Washington	RCV000031261	SCV001244042	not provided	Breast-ovarian cancer, familial 1		no assertion provided	in vitro