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 Lines of evidence used in support of classification: 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 colon cancer 2017-04-09 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 reported in individuals affected with colorectal cancer, and uterine and ovarian cancer (PMID: 16807412, 17414604, 25430799). ClinVar contains an entry for this variant (Variation ID: 90211). A different variant affecting  the initiator codon (c.1A>G and resulting in the same effect (p.Met?) has been determined to be pathogenic through the use of experimental studies investigating MMR activity and in-vitro protein expression (PMID: 24302565). Indicating that other substitutions at this position may also be pathogenic. In summary, this variant is a rare initiator codon variant that is expected to disrupt an important protein domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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