ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.3G>A (p.Met1Ile) (rs72481822)

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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) RCV000075700 SCV000106703 pathogenic Lynch syndrome I 2017-06-30 reviewed by expert panel curation meets criteria for Class 5
Ambry Genetics RCV000215403 SCV000275144 pathogenic Hereditary cancer-predisposing syndrome 2016-10-20 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence
Invitae RCV000554881 SCV000625153 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-24 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MLH1 mRNA. The next in-frame methionine is located at codon 35. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of Lynch syndrome (PMID: 16807412, 17414604). ClinVar contains an entry for this variant (Variation ID: 90211). This variant disrupts the p.Met1 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24302565, 11112663, 28944238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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