ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.114C>G (p.Asn38Lys) (rs267607706)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075121 SCV000106112 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Color RCV001176886 SCV001340975 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing
Invitae RCV001206557 SCV001377869 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 38 of the MLH1 protein (p.Asn38Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colon cancer (PMID: 18415027). ClinVar contains an entry for this variant (Variation ID: 89651). This variant has been reported to have conflicting or insufficient data to determine the effect on MLH1 protein function (PMID: 20020535, 22753075). This variant disrupts the p.Asn38 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12373605, 20704743, 27435373, 28514183, 26895986, 15713769). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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