ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.109G>C (p.Glu37Gln) (rs63751012)

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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 RCV000221562 SCV000275455 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000555996 SCV000625040 uncertain significance Hereditary nonpolyposis colon cancer 2017-07-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 37 of the MLH1 protein (p.Glu37Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 25420488). However, in that individual a truncating variant was also identified in cis in MLH1, and the impact of this c.109G>C variant is not known. ClinVar contains an entry for this variant (Variation ID: 231565). 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000664318 SCV000788254 likely pathogenic Lynch syndrome 2018-02-07 criteria provided, single submitter clinical testing The MLH1 p.E37K variant has been identified in an individual with a family history that meets current Amerstam criteria for Lynch syndrome. Testing performed on tumor tissue of a paitient with germline MLH1 p.E37K supports that this variant is likely pathogenic. Specifically, the germline MLH1 variant was detecting with loss of heterozygosity (LOH) of the second allele in the patient's tumor. Tumor screening showed the tissue was MSI-High with intact MLH1 protein expression by IHC. A different variant at the same codon of MLH1 (p.E37) has been observed as a double somatic mutation in a tumor tissue of a patient with endometrial adenocarcinoma that was microsatellite instability high, with intact MLH1 protein expression by IHC, and negative germline testing (UWMC internal data). This information suggests that mutations at codon 37 of the MLH1 protein may cause loss of protein function while leaving MLH1 protein staining intact on IHC. This variant has also been previously reported in a group of patients meeting Bethesda criteria, but occured in cis with a separate MLH1 frameshift mutation (PMID 25420488). This variant is not currently reported in population databases and occurs at a amino acid position that is conserved across species.

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