ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1415G>A (p.Arg472Lys) (rs63750498)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162406 SCV000212738 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000541695 SCV000625065 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 472 of the MLH1 protein (p.Arg472Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs63750498, ExAC 0.06%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 183714). 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 tolerated, 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.
Color RCV000162406 SCV000689812 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588918 SCV000696111 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1415G>A (p.Arg472Lys) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/121408 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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. One poster abstract reports the variant in a case of endometriosis-associated ovarian cancer, without strong evidence for causality. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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