Submissions for variant NM_002439.5(MSH3):c.2659G>A (p.Asp887Asn)

gnomAD frequency: 0.00006  dbSNP: rs546532182

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824602	SCV000965505	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 887 of the MSH3 protein (p.Asp887Asn). This variant is present in population databases (rs546532182, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 29868112). ClinVar contains an entry for this variant (Variation ID: 666167). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002453907	SCV002739468	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-21	criteria provided, single submitter	clinical testing	The p.D887N variant (also known as c.2659G>A), located in coding exon 20 of the MSH3 gene, results from a G to A substitution at nucleotide position 2659. The aspartic acid at codon 887 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Torrezan GT et al. Front Genet, 2018 May;9:161). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004569791	SCV005054796	uncertain significance	Endometrial carcinoma	2023-11-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000824602	SCV005623823	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The MSH3 c.2659G>A (p.Asp887Asn) variant has been reported in the published literature in an individual with early onset breast cancer (PMID: 29868112 (2018)). The frequency of this variant in the general population, 0.0002 (5/24938 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV005036232	SCV005666209	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751747	SCV005357130	uncertain significance	MSH3-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The MSH3 c.2659G>A variant is predicted to result in the amino acid substitution p.Asp887Asn. This variant has been reported in an individual with breast cancer (Torrezan et al. 2018. PubMed ID: 29868112). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. This variant is classified as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/666167/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.