ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.117T>G (p.Cys39Trp) (rs1305605404)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534762 SCV000625045 uncertain significance Hereditary nonpolyposis colon cancer 2017-03-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 39 of the MLH1 protein (p.Cys39Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000575029 SCV000664759 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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