ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.539T>C (p.Val180Ala) (rs63750102)

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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 RCV000131430 SCV000186411 uncertain significance Hereditary cancer-predisposing syndrome 2014-08-06 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
Integrated Genetics/Laboratory Corporation of America RCV000587902 SCV000696168 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.539T>C (p.Val180Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121366 control chromosomes from the large and broad populations of ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been classified as a variant of uncertain significance by a lab in ClinVar. Because of the absence of clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV001209337 SCV001380767 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 180 of the MLH1 protein (p.Val180Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 142349). 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. 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.

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