ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1377dup (p.Glu460fs)

dbSNP: rs63750020
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075183 SCV000106174 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV001059158 SCV001223770 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-04-20 criteria provided, single submitter clinical testing This variant has been observed in an individual affected with Lynch syndrome (PMID: 17653898). This variant is also known as c.1377_1378insA in the literature. ClinVar contains an entry for this variant (Variation ID: 89709). 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 is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu460Argfs*19) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics RCV002381379 SCV002699515 pathogenic Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing The c.1377dupA pathogenic mutation, located in coding exon 12 of the MLH1 gene, results from a duplication of A at nucleotide position 1377, causing a translational frameshift with a predicted alternate stop codon (p.E460Rfs*19). This alteration has been detected in the germline of someone diagnosed with colorectal or endometrial cancer showing the loss of MLH1 and PMS2 on immunohistochemistry (Rahner N et al. Acta Oncol, 2007;46:763-9). 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. RCV003451021 SCV004189935 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-20 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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