ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.704A>T (p.Asp235Val) (rs587781505)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129480 SCV000184250 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000529021 SCV000625188 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 235 of the MLH1 protein (p.Asp235Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (rs587781505, ExAC no frequency). This variant has been reported in an individual with colorectal cancer as well as in healthy controls (PMID: 23573243, 22216297). ClinVar contains an entry for this variant (Variation ID: 141115). 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, 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.
Color RCV000129480 SCV000684862 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing

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