BRCA1 NM_007294.4:c.5509T>G, Trp1837Gly

The p.W1837G variant (also known as c.5509T>G), located in coding exon 22 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5509. The tryptophan at codon 1837 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration is located in the BRCT domain of BRCA1. The tandem BRCA1 BRCT domain-phosphopeptide complex is involved in the DNA damage response in BRCA1 and alterations in this region which result in loss of phosphopeptide binding or weak binding abrogate BRCA1-BACH1 interaction and are responsible for cancer predisposition (Clapperton JA et al. Nat Struct Mol Biol. 2004 Jun;11(6):512-8). A peptide binding assay demonstrated that the p.W1837G alteration shows no detectable binding to biotinylated pSer-X-X-Phe peptides (Williams RS et al. Nat Struct Mol Biol. 2004 Jun;11(6):519-25). This alteration is structurally destabilizing and would result in a void within the BRCT domain (Williams RS et al. Nat Struct Mol Biol. 2004 Jun;11(6):519-25). A thermodynamic protein stability assay demonstrated that this alteration did not result in a stable protein but, rather, resulted in inclusion bodies, and was, in fact, classified as “very destabilizing” (Rowling PJ et al. J Biol Chem. 2010 Jun 25;285(26):20080-7). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). In addition, other functional assays confirm that the alteration is destabilizing and may cause a folding defect and predict a moderate functional impact that may increase cancer risk (Glover JN et al. Fam Cancer. 2006;5(1):89-93; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90). Another alteration at the same codon, p.W1837R, has been described in individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Montagna M et al. Cancer Res. 1996;56:5466-9; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481), and has also been predicted to be likely pathogenic and deleterious in several functional studies (Williams RS et al. J. Biol. Chem. 2003; 278:53007-16; Abkevich V et al. J. Med. Genet. 2004;41:492-507; Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Karchin R et al. PLoS Comput. Biol. 2007;3:e26; Lee MS et al. Cancer Res. 2010;70:4880-90; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Gaiser OJ et al. Biochemistry. 2004 Dec;43:15983-95). Of note, this alteration is also designated as 5628T>G in published literature. 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.

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1837 of the BRCA1 protein (p.Trp1837Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 16267036). ClinVar contains an entry for this variant (Variation ID: 55607). 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: 14534301, 15133503, 20378548, 20516115, 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.

This missense variant replaces tryptophan with glycine at codon 1837 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 reported that this variant abolishes BRCA1 function in phosphopeptide binding, transcription activation, and in a haploid cell proliferation assay, as well as disrupts the folding of the BRCT domain (PMID: 15133503, 20378548, 20516115, 29884841, 30209399). This variant has been reported in individuals who underwent BRCA gene testing (PMID: 10923033, 16267036). Different missense substitutions at this codon have been reported as disease-causing in ClinVar (variation ID: 37679, 37680, 853483, 1065962), and p.Trp1837Arg specifically has been reported in individuals and families affected with breast cancer and reported to segregate with disease in a family (PMID: 8968102, 11802209, 27741520, 28324225). 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.