Submissions for variant NM_000179.3(MSH6):c.2315G>A (p.Arg772Gln)

gnomAD frequency: 0.00002  dbSNP: rs63750725

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234432	SCV000283747	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 772 of the MSH6 protein (p.Arg772Gln). This variant is present in population databases (rs63750725, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal adenomas who also had a pathogenic MSH6 variant (PMID: 25985138). ClinVar contains an entry for this variant (Variation ID: 237155). 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 expected to disrupt MSH6 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg772 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14974087, 18176851, 23621914, 24323032, 25307252, 26333163, 28449805, 28514183; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV000418671	SCV000521710	uncertain significance	not provided	2019-09-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed as a germline variant in an individual with multiple adenomas who also carried an MSH6 nonsense variant (phase not determined), and as a somatic variant in a colon tumor exhibiting microsatellite instability in an individual with a germline MSH6 variant on the opposite allele (Ohmiya 2001, Taylor 2015); This variant is associated with the following publications: (PMID: 14974087, 18176851, 28514183, 11470537, 23621914, 25985138, 25307252, 8176851, 29548617, 24323032, 29887214)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758668	SCV000887439	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.2315G>A has a 63.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV001015160	SCV001175967	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	The p.R772Q variant (also known as c.2315G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2315. The arginine at codon 772 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a pathogenic MSH6 mutation (phase unknown) in an individual with an unspecified number of multiple adenomas (Taylor JC et al. Nat Genet. 2015 Jul;47(7):717-26). 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.
Color Diagnostics, LLC DBA Color Health	RCV001015160	SCV001354859	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 772 of the MSH6 protein. A different variant affecting the same position c.2314C>T (p.Arg772Trp) is considered to be disease-causing (ClinVar variation ID: 89267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual with multiple adenomas who also had a MSH6 nonsense mutation (PMID: 25985138). This variant has been identified in 5/282522 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2314C>T (p.Arg772Trp), is considered to be disease-causing (ClinVar variation ID: 89267), suggesting that this position is important for the protein function. 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.