ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.887T>G (p.Leu296Ter)

dbSNP: rs63750547
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075923 SCV000106940 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000484245 SCV000565148 pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.887T>G at the cDNA level and p.Leu296Ter (L296X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). MLH1 Leu296Ter has been reported in at least one individual with Lynch syndrome (Lee 2005). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000820731 SCV000961456 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-01-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in individuals affected with Lynch syndrome and colorectal cancer (PMID: 15996210, 28445943). ClinVar contains an entry for this variant (Variation ID: 90430). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu296*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics RCV003362686 SCV004053405 pathogenic Hereditary cancer-predisposing syndrome 2023-06-15 criteria provided, single submitter clinical testing The p.L296* pathogenic mutation (also known as c.887T>G), located in coding exon 11 of the MLH1 gene, results from a T to G substitution at nucleotide position 887. This changes the amino acid from a leucine to a stop codon within coding exon 11. This mutation has been reported in multiple individuals who meet Amsterdam II criteria and/or have mismatch repair deficient colorectal cancer (Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Yang M et al. Ther Adv Med Oncol, 2021 Jun;13:17588359211023290; Jiang W et al. Int J Cancer, 2019 May;144:2161-2168; Lee SC et al. Clin Genet, 2005 Aug;68:137-45). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV003452787 SCV004188726 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-18 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.
3DMed Clinical Laboratory Inc RCV000677881 SCV000804042 pathogenic Colon cancer 2018-03-08 no assertion criteria provided clinical testing

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