ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1569G>T (p.Glu523Asp) (rs63751680)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552506 SCV000625081 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 523 of the MLH1 protein (p.Glu523Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89792). An experimental study has shown that this missense change does not affect MLH1 protein function in vitro or in yeast-based assays (PMID: 17510385). In summary, this variant is a rare missense change that has been shown to preserve protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000562703 SCV000669517 likely benign Hereditary cancer-predisposing syndrome 2016-06-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000589315 SCV000696117 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1569G>T (p.Glu523Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Two functional studies showed that the mutation is not localized in, and does not create or disrupt any regulatory sequence (Lastella_BMC Genomics_2006) and that this variant maintained 76.6% in vitro MMR activity with >75% relative MLH1 expression (Takahashi_Cancer Res_2007). The neutrality of this variant has been suggested by computational studies (Chao_MSH2-MLH1_HM_2008, Lastella_BMC Genomics_2006). The variant of interest has not been found in a large, broad control population, ExAC in 121250 control chromosomes. One reputable database classified this variant as uncertain significance. The variant is classified as VUS until more functional studies and/or clinical information become available.
Color RCV000562703 SCV000908636 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000589315 SCV000977383 likely benign not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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