ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1046dup (p.Pro350fs)

dbSNP: rs267607822
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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) RCV000075099 SCV000106091 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000166148 SCV000216920 pathogenic Hereditary cancer-predisposing syndrome 2023-07-20 criteria provided, single submitter clinical testing The c.1046dupT pathogenic mutation, located in coding exon 12 of the MLH1 gene, results from a duplication of T at nucleotide position 1046, causing a translational frameshift with a predicted alternate stop codon (p.P350Tfs*12). This mutation was identified in a large family, in which nine members were affected with colorectal cancer, two with colon polyps, three with skin cancer, and one with endometrial cancer (Middeldorp A et al. BMC Cancer. 2007;7:6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae RCV000694270 SCV000822706 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-05-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89630). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 17222328). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro350Thrfs*12) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).
Myriad Genetics, Inc. RCV003451001 SCV004186340 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-19 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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