ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 23621914, 26689913, 29338689, 31386297)

This missense variant replaces lysine with arginine at codon 646 of the MSH6 protein. Computational prediction tool 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 performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26689913, 30982232), and in an individual affected with endometrial cancer that did not meet Amsterdam II criteria or revised Bethesda guidelines (PMID: 31307542). This variant has been identified in 9/251204 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.

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.

Variant summary: MSH6 c.1937A>G (p.Lys646Arg) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function, in addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui 2013). The variant allele was found at a frequency of 3.6e-05 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00043 in the gnomAD database, which is higher than the expected maximum for a pathogenic variant in MSH6 (0.00014), supporting a benign role for the variant. c.1937A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Lu_2015, Wang_2019, Samuel_2019, Yehia_2018), and one of these individuals had a positive family history for colon cancer (Samuel_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6, p.K1228fs*2), providing supporting evidence for a benign role (Yehia_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant replaces lysine with arginine at codon 646 of the MSH6 protein. Computational prediction tool 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 performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26689913, 30982232), and in an individual affected with endometrial cancer that did not meet Amsterdam II criteria or revised Bethesda guidelines (PMID: 31307542). This variant has been identified in 9/251204 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.

The MSH6 p.Lys646Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs201096652) as “With Uncertain significance allele”, in ClinVar and Clinvitae (classified as uncertain significance by Invitae, GeneDx and Color Genomics; and likely benign by Ambry Genetics), and COSMIC databases (confirmed somatic in one case of gastric adenocarcinoma). The variant was identified in control databases in 8 of 245948 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 7 of 17248 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003) while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, or Finnish populations. The p.Lys646 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.