ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability 0.001-0.049

Variant summary: MSH6 c.161G>C (p.Gly54Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 176940 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.161G>C has been reported in the literature in one individual affected with Colorectal Cancer with positive MSH6 on IHC and MSS tumor (Peterlongo_2003) as well as in patients with breast/ovarian cancer without strong evidence for causality (Pal_2012, Tung_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: five have classified the variant as likely benign, two as benign, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is associated with the following publications: (PMID: 14520694, 23047549, 22290698, 23621914, 24933000, 26332594)

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

In the published literature, this variant has been identified in individuals with ovarian cancer and colorectal cancer (PMIDs: 14520694 (2003), 23047549 (2012)). Internal laboratory indicates that this variant was observed with a pathogenic variant in the MUTYH gene, suggesting that this variant may not be the primary cause of disease. The frequency of this variant in the general population, 0.000055 (4/72210 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

The p.Gly54Ala variant in MSH6 has been reported in 1 individuals with colorectal cancer (Peterlongo 2013) and in 1 individual with ovarian cancer (Pal 2012). It has also been identified in 4/72210 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Likely benign on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89208). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity (Ali 2012, Terui 2013). In vivo functional studies provide some evidence that this variant does not impact protein function (Peterlong 2013). In summary, the p.Gly54Ala variant is classified as Likely Benign. ACMG/AMP criteria applied: BS3, BP4.