ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1613G>A (p.Trp538Ter)

dbSNP: rs587778933
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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) RCV000075276 SCV000106270 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000545817 SCV000625083 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-06-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89802). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 22883484). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp538*) 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).
Ambry Genetics RCV000567360 SCV000669624 pathogenic Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing The p.W538* pathogenic mutation (also known as c.1613G>A), located in coding exon 14 of the MLH1 gene, results from a G to A substitution at nucleotide position 1613. This changes the amino acid from a tryptophan to a stop codon within coding exon 14. This mutation was reported in an individual with a history of colorectal, bladder and renal pelvis cancer. The renal pelvis tumor demonstrated microsatellite instability and absence of MLH1 on immunohistochemistry (Skeldon SC et al. Eur. Urol. 2013 Feb;63:379-85). 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, Inc. RCV003451040 SCV004190061 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-20 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.

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