ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 23047549, 30521064, 30093976)

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.

The p.Asn1327Ser variant in MSH6 has been reported in one individual with ovaria n cancer (Pal 2012) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 220943). Additionally, it has been identified in 16/1874 0 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computati onal prediction tools and conservation analysis suggest that the p.Asn1327Ser va riant may not impact the protein. In summary, the clinical significance of the p.Asn1327Ser variant is uncertain. ACMG/AMP Criteria applied: BP4.

Variant summary: MSH6 c.3980A>G (p.Asn1327Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246806 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3980A>G has been reported in the literature in at least one individual affected with Lynch Syndrome (Jiang_2019), as well as a VUS in settings of multigene panel testing among individuals affected with epithelial ovarian cancer (Pal_2012) and breast cancer (Chan_2018). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 30521064, 23047549, 35171259, 36243179). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

This missense variant replaces asparagine with serine at codon 1327 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 30521064), or breast cancer (PMID: 30093976). This variant has been identified in 18/278198 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.