ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.292_293delinsTT (p.Gly98Phe) (rs1553640314)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000630134 SCV000751090 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with phenylalanine at codon 98 of the MLH1 protein (p.Gly98Phe). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and phenylalanine. 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. 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. A different missense substitution at this codon (p.Gly98Ser) has been reported in individuals affected with suspected Lynch syndrome (PMID: 22290698, 185612205), and has been shown to segregate with Lynch syndrome-associated cancers in several families (Invitae). This suggests that the glycine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be damaging. 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.
Ambry Genetics RCV001017507 SCV001178595 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence;Well-characterized mutation at same position

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