ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2315G>A (p.Arg772Gln) (rs63750725)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234432 SCV000283747 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 772 of the MSH6 protein (p.Arg772Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63750725, ExAC 0.003%). This variant has been reported in an individual affected with multiple adenomas (PMID: 25985138). However, a pathogenic allele also was identified in the MSH6 gene, which suggests that this c.2315G>A substitution in MSH6 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 237155). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg772 amino acid residue in MSH6 have been observed in affected individuals (PMID: 8176851, 25307252, 14974087, 28514183, 24323032). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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 2017-07-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2315G>A at the cDNA level, p.Arg772Gln (R772Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was reported in an individual with multiple adenomas who also harbored an MSH6 nonsense variant but phase was not determined (Taylor 2015). MSH6 Arg772Gln was also reported as a somatic variant in stomach and colon tumors with microsatellite instability, with one individual found to have MSH6 Val878Ala as a germline variant on the opposite allele (Ohmiya 2001). MSH6 Arg772Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg772Gln occurs at a position that is conserved across species and is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, it is unclear whether MSH6 Arg772Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 2019-08-20 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001015160 SCV001354859 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing

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