ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.122A>T (p.Asp41Val) (rs63751094)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571853 SCV000673820 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Invitae RCV000553834 SCV000625050 likely pathogenic Hereditary nonpolyposis colon cancer 2017-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 41 of the MLH1 protein (p.Asp41Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. It has been observed in two affected individuals in a single family with Lynch syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different variant (c.122_123delATinsTA), giving rise to the same protein effect observed here (p.Asp41Val), has been reported in a family affected with Lynch syndrome (PMID: 19419416), as well as an individual affected with gastrointestinal cancer (PMID: 23760103). This indicates that this residue may be critical for protein function. A different missense substitution at this codon (p.Asp41His) has been determined to be pathogenic (PMID: 12624141, 25060679, 25477341). This suggests that the aspartic acid residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. 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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