Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075706 | SCV000106710 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Invitae | RCV000551153 | SCV000625162 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2017-03-30 | 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. This particular variant has been reported in the literature in individuals affected with Lynch syndrome (PMID: 11754112, 12555990). This sequence change creates a premature translational stop signal at codon 146 (p.Gln146*) of the MLH1 gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV002326788 | SCV002627612 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | The p.Q146* pathogenic mutation (also known as c.436C>T), located in coding exon 5 of the MLH1 gene, results from a C to T substitution at nucleotide position 436. This changes the amino acid from a glutamine to a stop codon within coding exon 5. In a study of 1,721 German probands suspected of HNPCC, this mutation was detected in one family (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This mutation has also been reported in a family with HNPCC where the proband had multiple colorectal cancers, and tumor screening demonstrated absence of MLH1 protein expression and microsatellite instability (Krüger S et al. Hum. Mutat., 2002 Jan;19:82). 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. |
| Myriad Genetics, |
RCV004019104 | SCV004933204 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2024-03-29 | 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. |