Submissions for variant NM_002439.5(MSH3):c.2262A>G (p.Ile754Met)

gnomAD frequency: 0.00028  dbSNP: rs200819607

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815096	SCV000955540	uncertain significance	not provided	2025-01-29	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 754 of the MSH3 protein (p.Ile754Met). This variant is present in population databases (rs200819607, 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: 658298). 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	RCV001014973	SCV001175752	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	The p.I754M variant (also known as c.2262A>G), located in coding exon 16 of the MSH3 gene, results from an A to G substitution at nucleotide position 2262. The isoleucine at codon 754 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV001816893	SCV002069771	uncertain significance	not specified	2021-07-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH3 gene demonstrated a sequence change, c.2262A>G, in exon 16 that results in an amino acid change, p.Ile754Met. This sequence change has been described in the gnomAD database with a frequency of 0.13% in the Finnish European subpopulation (dbSNP rs200819607). The p.Ile754Met change affects a moderately conserved amino acid residue located in a domain of the MSH3 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile754Met substitution. This sequence change does not appear to have been previously described in individuals with MSH3-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile754Met change remains unknown at this time.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001816893	SCV002550516	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000815096	SCV002563840	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	MSH3: BP1
GeneDx	RCV000815096	SCV002586982	uncertain significance	not provided	2024-11-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34465320, 37453563)
Baylor Genetics	RCV003461231	SCV004196956	uncertain significance	Endometrial carcinoma	2024-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000815096	SCV004221069	likely benign	not provided	2023-07-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005036200	SCV005666200	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-04-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003413642	SCV004118123	uncertain significance	MSH3-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The MSH3 c.2262A>G variant is predicted to result in the amino acid substitution p.Ile754Met. This variant has been detected, among with other variants of uncertain significance, in the primary tumor of patient with familial chordoma (Sumransub et al. 2021. PubMed ID: 34465320). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely benign and uncertain in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/658298). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.