ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.218T>G (p.Leu73Arg) (rs397514684)

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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 RCV000213759 SCV000274574 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000466354 SCV000543534 uncertain significance Lynch syndrome 2016-10-04 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 73 of the MLH1 protein (p.Leu73Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (rs397514684, ExAC no frequency). This variant has been reported as being homozygous in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 22692065). ClinVar contains an entry for this variant (Variation ID: 42192). Experimental studies have shown that this mutant causes loss of mismatch repair activity in vitro (PMID: 22692065). In summary, this variant is a rare missense change which has been shown to impair protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000035016 SCV000058656 pathogenic Turcot syndrome 2013-01-01 no assertion criteria provided literature only

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