ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.204C>G (p.Ile68Met) (rs780141938)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566410 SCV000676042 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000695466 SCV000823968 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 68 of the MLH1 protein (p.Ile68Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs780141938, ExAC 0.002%). This variant has been observed in an individual affected with colorectal cancer (PMID: 25435955). ClinVar contains an entry for this variant (Variation ID: 486852). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Ile68Asn amino acid residue in MLH1 has been determined to be clinically significant (PMID: 24362816, 14961575, 11304573, 17510385, 11555625, 10082584, 12810663). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.
Mendelics RCV000708913 SCV000837995 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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