ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2250C>G (p.Tyr750Ter) (rs267607893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075585 SCV000592446 pathogenic Lynch syndrome 2016-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000482247 SCV000565173 likely pathogenic not provided 2015-07-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2250C>G at the cDNA level and p.Tyr750Ter (Y750X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG). This variant is, the last exon of the gene, and results in protein truncation and loss of 7 amino acids. MLH1 Tyr750Ter has been observed in at least two individuals with colorectal cancer and in at least one HNPCC family (Syngal 1999, Wang 2006, Mueller 2009). In a mouse embryonic fibroblast model, this variant was associated with MLH1 expression levels similar to wild type, but reduced levels of PMS2, which was described as indicating an inability to stabilize PMS2 protein (Mohd 2006). Similar results were also demonstrated in an in vitro human cell line study, which further reported that MLH1 Tyr750Ter was associated with significantly reduced, but not entirely eliminated, mismatch repair activity (Kosinski 2010). We therefore consider MLH1 Tyr750Ter to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075585 SCV000106582 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence: premature termination codon outside of known functional domain

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