ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2027T>C (p.Leu676Pro) (rs63750242)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216198 SCV000275857 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbSNP, ESP, 1000 Genomes),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or Conflicting Evidence
Invitae RCV000695668 SCV000824182 uncertain significance Hereditary nonpolyposis colon cancer 2018-03-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 676 of the MLH1 protein (p.Leu676Pro). The leucine residue is weakly 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 reported in individuals affected with Lynch syndrome (PMID: 21404117, 28874130, 26437257). ClinVar contains an entry for this variant (Variation ID: 90001). Experimental studies in yeast have shown that this missense change causes defects in mismatch repair activity, interaction with PMS2, and expression of the MLH1 protein (PMID: 21404117). However, studies using human colon carcinoma cell lines have reported conflicting data, showing no effects on the PMS2 interaction and normal subcellular localization of the MLH1 protein (PMID: 26437357). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075485 SCV000914325 uncertain significance Lynch syndrome 2019-01-30 criteria provided, single submitter research

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