ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1998G>A (p.Trp666Ter)

dbSNP: rs63750639
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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) RCV000075473 SCV000106470 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx 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.

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