BRCA1 NM_007294.3:c.5522G>A, Ser1841Asn

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822, 35918668). ClinVar contains an entry for this variant (Variation ID: 55613). 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: 16786532, 16969499, 17005433, 20378548, 25748678, 28781887, 30209399, 30257991, 30765603). This variant disrupts the p.Ser1841 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20516115, 23522120, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The BRCA1 c.5522G>A (p.Ser1841Asn) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 35918668 (2022), 29752822 (2018), 28364669 (2017)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 30765603 (2019), 30209399 (2018), 28781887 (2016), 20516115 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5522. The serine at codon 1841 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in cohorts of breast and ovarian cancer patients (Ryu JM et al. Breast, 2017 Jun;33:109-116; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has been shown to have a detrimental effect on protein stability, structure, and binding in functional assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69), and was determined to be deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, p.S1841N is highly disruptive to this region of BRCA1 (Ambry internal data; Gaiser OJ et al. Biochemistry. 2004 Dec;43(51):15983-95). 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 majority of available evidence to date, this variant is likely to be pathogenic.