ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1744C>G (p.Leu582Val) (rs63751713)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627697 SCV000543553 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 582 of the MLH1 protein (p.Leu582Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs63751713, ExAC 0.01%). This variant has been reported in a family affected with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 7757073). ClinVar contains an entry for this variant (Variation ID: 89869). Experimental studies have shown that this missense change does not adversely affect protein function (PMID: 10037723, 17510385, 15864295, 12810663), although not all of the studies are in agreement (PMID: 9697702). 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 RCV000571505 SCV000662046 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000571505 SCV000908644 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-25 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030630 SCV001193612 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001193957 SCV001363153 uncertain significance not specified 2019-08-05 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1744C>G (p.Leu582Val) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1744C>G has been reported in the literature in individuals from at-least one family with Lynch Syndrome (Han_1995). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Several publications report experimental evidence evaluating an impact on protein function. These results reproducibly reported no damaging effect of this variant on measures of interaction with PMS2, in-vitro MMR activity, and interaction with hMRE11 (Guerrette_1999, Takahashi_2007, Vo_2005, Kondo_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. One expert panel in ClinVar (InSIGHT) has classified this variant as uncertain significance with an evaluation dating to 2013. Based on the evidence outlined above, the variant was classified as uncertain significance.

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