ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1958T>C (p.Leu653Pro) (rs63751202)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200648 SCV000254365 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 653 of the MLH1 protein (p.Leu653Pro). 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 several individuals affected with Lynch syndrome (Invitae). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. This variant disrupts the p.Leu653 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17510385, 21952876, 17210669, 23403630, 22949379). 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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