Submissions for variant NM_000179.3(MSH6):c.2899A>G (p.Ile967Val)

dbSNP: rs876661067

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657064	SCV000279446	uncertain significance	not provided	2018-03-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2899A>G at the cDNA level, p.Ile967Val (I967V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile967Val was not observed in large population cohorts (Lek 2016). This variant is located in the clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Ile967Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000461768	SCV000551154	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-10	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: 234533). 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 isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 967 of the MSH6 protein (p.Ile967Val).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214691	SCV000601545	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573070	SCV000670023	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The p.I967V variant (also known as c.2899A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2899. The isoleucine at codon 967 is replaced by valine, an amino acid with highly similar properties. 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000214691	SCV002518280	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153515	SCV003843821	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998622	SCV004821459	uncertain significance	Lynch syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 967 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.