ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1865T>C (p.Leu622Pro) (rs63750693)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075390 SCV000106385 pathogenic Lynch syndrome 2019-02-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99 (1.000)
Invitae RCV001201390 SCV000254361 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 622 of the MLH1 protein (p.Leu622Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21404117, 1749856, Invitae). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Additionally, an algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. This variant disrupts the p.Leu622 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20858721, 23403630, 24362816, 17510385, 11748856). 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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