Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
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, |
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, |
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/). |