Submissions for variant NM_002439.5(MSH3):c.3000T>G (p.Asp1000Glu)

gnomAD frequency: 0.00010  dbSNP: rs139205893

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816940	SCV000957469	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1000 of the MSH3 protein (p.Asp1000Glu). This variant is present in population databases (rs139205893, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 659866). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV001017990	SCV001179163	likely benign	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV001017990	SCV002536098	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
GeneDx	RCV000816940	SCV003924581	uncertain significance	not provided	2022-11-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28740175)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320218	SCV004024354	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000816940	SCV004221090	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00048 (12/24958 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004569724	SCV005053565	uncertain significance	Endometrial carcinoma	2024-03-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005047104	SCV005666218	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-05-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003948004	SCV004761477	likely benign	MSH3-related disorder	2024-02-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).