ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2250C>A (p.Tyr750Ter)

dbSNP: rs267607893
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075584 SCV000106581 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Insufficient evidence: premature termination codon outside of known functional domain; Nonsense variant after codon 743 in MLH1 = VUS
Invitae RCV001854299 SCV002229931 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-09-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects MLH1 function (PMID: 20533529). ClinVar contains an entry for this variant (Variation ID: 90098). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20233461). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr750*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the MLH1 protein.
Myriad Genetics, Inc. RCV003451118 SCV004186456 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-25 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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