ClinVar Genomic variation as it relates to human health

The p.Arg468Cys variant in MSH6 has been reported in one individual with suspected Lynch syndrome (Yurgelun 2015 PMID 25980754). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 89191) and has been identified in 0.003% (3/113504) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg468Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg468Cys variant is uncertain. ACMG criteria applied: PM2, PP3.

This missense variant replaces arginine with cysteine at codon 468 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 been reported in individuals with Lynch syndrome-associated cancers whose tumors exhibited microsatellite stability or normal mismatch repair protein expression via immunohistochemistry analysis (ClinVar SCV000217287.8), as well as an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 3/251136 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.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23621914, 26333163, 29887214, 29581542, 31159747, 30798936, 27363726, 25980754, 36243179, 25186627, 30267214, 31422818, 17531815, 21120944)

Variant summary: MSH6 c.1402C>T (p.Arg468Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) 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 1.2e-05 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1402C>T has been reported in the literature in individuals screened for Hereditary Nonpolyposis Colorectal Cancer (e.g. Yurgelun_2015, Gordon_2019) and Hereditary Breast and Ovarian Cancer (e.g. Tung_2015, Tsaousis_2019) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 468 of the MSH6 protein (p.Arg468Cys). This variant is present in population databases (rs369456858, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25186627, 25980754, 31159747, 31422818). ClinVar contains an entry for this variant (Variation ID: 89191). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). 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.

The p.R468C variant (also known as c.1402C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1402. The arginine at codon 468 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in a cohort of 1260 patients with a Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149(3):604-13.e20). In addition, this alteration was detected in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant has been identified in multiple probands whose Lynch syndrome-associated tumor was microsatellite stable or demonstrated normal mismatch repair protein expression by immunohistochemistry (Ambry internal data). 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.

MSH6 NM_000179.2:c.1402C>T has a 64.4% 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.

The MSH6 c.1402C>T variant is predicted to result in the amino acid substitution p.Arg468Cys. This variant has been reported as a variant of uncertain significance in individuals with a personal or family history of Lynch Syndrome (Table S2, Yurgelun. 2015, PubMed ID: 25980754; Gordon. 2019. PubMed ID: 31422818). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026524-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89191/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Uncertain significance and reported on 09-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.