ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2206G>T (p.Glu736Ter) (rs876659608)

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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 RCV000219289 SCV000276253 pathogenic Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000255736 SCV000321901 pathogenic not provided 2015-04-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.2206G>T at the cDNA level and p.Glu736Ter (E736X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in at least one individual with colorectal cancer (Bozzao 2011, Lastella 2011) and is considered pathogenic.
Invitae RCV000535128 SCV000625134 pathogenic Hereditary nonpolyposis colon cancer 2017-07-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MLH1 gene (p.Glu736*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 21 amino acids of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 21286823). ClinVar contains an entry for this variant (Variation ID: 232190). While no functional studies have been performed to test the effect of this particular variant on MLH1 protein function or stability, it affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). A different nonsense variant, p.Tyr750*, located downstream of this variant has been shown to significantly affect PMS2-MLH1 dimerization and mismatch repair activity (PMID: 16338176, 20533529), and has been reported in an individual affected with Lynch syndrome (PMID: 10422993). This suggests that the MLH1 CTD region disrupted by this variant is critical for MLH1 function. For these reasons, this variant has been classified as Pathogenic.

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