ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.364G>A (p.Glu122Lys) (rs143036974)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160719 SCV000215491 uncertain significance Inborn genetic diseases 2016-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Color RCV000776349 SCV000911715 likely benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Counsyl RCV000411966 SCV000487888 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000212630 SCV000211353 uncertain significance not provided 2018-02-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.364G>A at the cDNA level, p.Glu122Lys (E122K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu122Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Glu122Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780470 SCV000917743 likely benign not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.364G>A (p.Glu122Lys) results in a conservative amino acid change located in the PWWP domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting the variant is a benign polymorphism found primarily in populations of Latino origin. The c.364G>A variant has been reported in two publications without strong evidence for pathogenicity; thus, these reports do not provide unequivocal conclusions about an association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All of these laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000197561 SCV000254318 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 122 of the MSH6 protein (p.Glu122Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs143036974, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182662). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.

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