Submissions for variant NM_000179.3(MSH6):c.2927G>A (p.Arg976His)

dbSNP: rs63751113

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218618	SCV000273877	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The p.R976H variant (also known as c.2927G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2927. The arginine at codon 976 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in individuals diagnosed with colorectal cancers demonstrating isolated loss/reduced staining of MSH6 on immunohistochemistry (Plaschke J et al. Int. J. Cancer, 2002 Feb;97:643-8; Salvador MU et al. J Clin Oncol. 2019 Mar 10;37(8):647-657). Additionally, functional studies have concluded that this variant affects mismatch repair recognition, demonstrating the MMR activity of p.R976H to be less than 50% compared to wild type (Cyr JL et al. J. Biol. Chem., 2008 Nov;283:31641-8; Drost M et al. Hum. Mutat., 2012 Mar;33:488-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455514	SCV000539703	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: VUS by expert panel; No new info since expert classification
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000455514	SCV000601547	uncertain significance	not specified	2017-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV000629775	SCV000750731	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 976 of the MSH6 protein (p.Arg976His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Lynch syndrome, autosomal recessive constitutional mismatch repair deficiency syndrome, and/or clinical features of Lynch syndrome (PMID: 11807791, 28514183, 30702970, 31391288; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89322). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. Experimental studies have shown that this missense change affects MSH6 function (PMID: 18790734, 22102614). This variant disrupts the p.Arg976 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (PMID: 29755653, 30702970), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV002273954	SCV002559283	likely pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: moderate impact on mismatch binding and repair activity, reduced ATP and ADP binding ability (Cyr et al., 2008; Drost et al., 2012); This variant is associated with the following publications: (PMID: 22102614, 31552911, 11807791, 23621914, 30702970, 34445333, 18790734, 24362816, 21120944, 17531815, 26333163, 31391288, 28514183)
Baylor Genetics	RCV003460673	SCV004198132	likely pathogenic	Endometrial carcinoma	2022-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218618	SCV004357682	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 976 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies report that this variant has ~50% mismatch-repair activity in a cell-free assay (PMID: 22102614) and reduced DNA and ATP binding activity (PMID: 18790734). This variant has been reported in an individual affected with Lynch syndrome (PMID: 30702970) and in an individual affected with colorectal and kidney cancer that demonstrated loss of MSH6 protein expression by immunohistochemistry analysis (PMID: 11807791). 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.