ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.910G>T (p.Asp304Tyr) (rs1482654951)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528302 SCV000625207 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-07-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 304 of the MLH1 protein (p.Asp304Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant was observed to segregate with colorectal cancer in a single family (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 missense substitution at this codon (p.Asp304Val) has been determined to be pathogenic (PMID: 10882759, 21952876, 17510385, 24362816). 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, this variant is a novel missense change with uncertain impact on protein function that has been shown to segregate with disease in a family. A different missense substitution at this codon has been determined to be deleterious. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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