ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.112A>T (p.Asn38Tyr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001228630 SCV001401038 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 38 of the MLH1 protein (p.Asn38Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of Lynch syndrome in a 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 and their clinical significance is uncertain. This variant disrupts the p.Asn38 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12373605, 20704743, 27435373, 28514183, 20020535, 23403630). 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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