Submissions for variant NM_002439.5(MSH3):c.2016T>G (p.Ile672Met)

gnomAD frequency: 0.00046  dbSNP: rs139593361

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794249	SCV000933643	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 672 of the MSH3 protein (p.Ile672Met). This variant is present in population databases (rs139593361, gnomAD 0.1%). 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: 641087). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001014064	SCV001174725	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-17	criteria provided, single submitter	clinical testing	The p.I672M variant (also known as c.2016T>G), located in coding exon 14 of the MSH3 gene, results from a T to G substitution at nucleotide position 2016. The isoleucine at codon 672 is replaced by methionine, an amino acid with highly similar properties. This variant has been identified in an individual diagnosed with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Sema4, Sema4	RCV001014064	SCV002536024	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
GeneDx	RCV000794249	SCV002558677	uncertain significance	not provided	2022-01-28	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; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards 2015)
Fulgent Genetics, Fulgent Genetics	RCV002507368	SCV002815532	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2021-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003413591	SCV004113910	uncertain significance	MSH3-related disorder	2023-05-12	criteria provided, single submitter	clinical testing	The MSH3 c.2016T>G variant is predicted to result in the amino acid substitution p.Ile672Met. This variant has been reported as a variant of uncertain significance in a patient with breast cancer (Table S4 - Sandoval et al. 2021. PubMed ID: 33606809). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-80063871-T-G) and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/641087/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000794249	SCV004221060	uncertain significance	not provided	2024-03-23	criteria provided, single submitter	clinical testing	The MSH3 c.2016T>G (p.Ile672Met) variant has been reported in at least one individual with breast cancer (PMID: 33606809 (2021)). The frequency of this variant in the general population, 0.0013 (32/24950 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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.