ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1855G>C (p.Ala619Pro) (rs267607866)

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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) RCV000075387 SCV000106383 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics RCV000165622 SCV000216358 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000548274 SCV000625103 likely pathogenic Hereditary nonpolyposis colon cancer 2019-01-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 619 of the MLH1 protein (p.Ala619Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with suspected or reported Lynch syndrome (PMID: 21404117, 18561205, 28514183, 10612827, 21520333). It has also been observed to segregate with colon cancer in a family (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 89909). 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: "Benign"; Align-GVGD: "Class C0"). 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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