Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000075473 | SCV000106470 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
Gene |
RCV000627203 | SCV000748190 | pathogenic | not provided | 2018-02-22 | criteria provided, single submitter | clinical testing | This variant is denoted MLH1 c.1998G>A at the cDNA level and p.Trp666Ter (W666X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals with a personal and family history of Lynch-related cancers (Rossi 2002, Taylor 2003) and is considered pathogenic. |
Ambry Genetics | RCV002415529 | SCV002721766 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-12 | criteria provided, single submitter | clinical testing | The p.W666* pathogenic mutation (also known as c.1998G>A), located in coding exon 18 of the MLH1 gene, results from a G to A substitution at nucleotide position 1998. This changes the amino acid from a tryptophan to a stop codon within coding exon 18. This mutation has been reported in multiple Lynch syndrome families, including at least one meeting Amsterdam II criteria (Rossi BM et al. Ann. Surg. Oncol., 2002 Jul;9:555-61; Taylor CF et al. Hum. Mutat., 2003 Dec;22:428-33). 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 | RCV002514344 | SCV003525137 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-29 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 89991). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12095971). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp666*) 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). For these reasons, this variant has been classified as Pathogenic. |