ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Invitae RCV000197561 SCV000254318 likely benign Hereditary nonpolyposis colon cancer 2019-12-18 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
Color RCV000776349 SCV000911715 likely benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
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.
Ambry Genetics RCV000776349 SCV001182330 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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