Submissions for variant NM_000179.3(MSH6):c.2372G>A (p.Arg791His)

dbSNP: rs755587950

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219569	SCV000273107	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.R791H variant (also known as c.2372G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2372. The arginine at codon 791 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in a cohort of 72 cases of hereditary breast/ovarian cancer and 57 hereditary non-polyposis colorectal cancer patients in Spain (Velázquez C et al. J Transl Med, 2020 Jun;18:232). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470330	SCV000551287	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	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 791 of the MSH6 protein (p.Arg791His). This variant is present in population databases (rs755587950, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 229774). 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%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000219569	SCV000908398	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 791 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). 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 been identified in 1/250954 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282050	SCV002570525	uncertain significance	not specified	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2372G>A (p.Arg791His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250954 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2372G>A has been reported in the literature in an individual who went through panel testing (35 genes) for inherited cancer (example: Valazquez_2020). This individual also had a pathogenic co-occurrence (PMS2 c.137G>T, p.Ser46Ile), providing supporting evidence for a benign role (example: Valazquez_2020). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997769	SCV004834276	uncertain significance	Lynch syndrome	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 791 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). 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 been identified in 1/250954 chromosomes 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.
GeneDx	RCV004589913	SCV005079117	uncertain significance	not provided	2023-12-05	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; Co-occurred with a pathogenic PMS2 variant in an individual with either hereditary breast/ovarian cancer or hereditary non-polyposis colorectal cancer (PMID: 32522261); This variant is associated with the following publications: (PMID: 32522261, 17531815, 21120944)