Submissions for variant NM_000179.3(MSH6):c.419G>T (p.Arg140Met)

dbSNP: rs876661293

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214200	SCV000280004	uncertain significance	not provided	2016-03-18	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.419G>T at the cDNA level, p.Arg140Met (R140M) at the protein level, and results in the change of an Arginine to a Methionine (AGG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg140Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg140Met occurs at a position that is conserved across species and is located in the PWWP domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg140Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526661	SCV000624968	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-04	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 234916). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 140 of the MSH6 protein (p.Arg140Met).
Ambry Genetics	RCV002327097	SCV002626665	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The p.R140M variant (also known as c.419G>T), located in coding exon 2 of the MSH6 gene, results from a G to T substitution at nucleotide position 419. The arginine at codon 140 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004567688	SCV005055019	uncertain significance	Endometrial carcinoma	2023-11-29	criteria provided, single submitter	clinical testing