ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.545G>C (p.Arg182Thr) (rs587779021)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000698424 SCV000827085 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 182 of the MLH1 protein (p.Arg182Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 6 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast and colon cancers (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000210209 SCV000266074 likely pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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