ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2016T>G (p.Cys672Trp) (rs1312172811)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553559 SCV000625116 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 672 of the MLH1 protein (p.Cys672Trp). 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). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2016T>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 455413). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing. However RT-PCR analysis of cells from the individual reported in the Universal Mutation Database resulted in normal splicing (PMID: 23729658). These results have not been published in the literature. 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 RCV000562503 SCV000673844 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562503 SCV001352560 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-01 criteria provided, single submitter clinical testing

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