ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.982C>T (p.Gln328Ter)

dbSNP: rs587779058
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075952 SCV000106970 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000166394 SCV000217186 pathogenic Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing The p.Q328* pathogenic mutation (also known as c.982C>T), located in coding exon 11 of the MLH1 gene, results from a C to T substitution at nucleotide position 982. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was detected in a patient with endometrial cancer that showed loss of MLH1 and PMS2 staining by IHC and had a family history meeting Amsterdam criteria (Ambry internal data). This mutation has also been identified in a patient undergoing multi-gene panel testing for a personal and/or family history of cancer (Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). 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 RCV001383394 SCV001582527 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-06-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln328*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual who underwent multigene panel testing (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 90458). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV003452792 SCV004186530 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.
All of Us Research Program, National Institutes of Health RCV000075952 SCV004822621 pathogenic Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in individuals with MLH1-related cancer or referred for genetic testing due to personal/family history of cancer (PMID: 28514183, 22160601). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

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