ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2239A>T (p.Arg747Ter)

dbSNP: rs1554294448
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000607235 SCV000711445 pathogenic Lynch syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Arg747X variant in PMS2 has not been previously reported in individuals wi th Lynch syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 747, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is a n established disease mechanism in Lynch syndrome. In summary, this variant meet s criteria to be classified as pathogenic for Lynch syndrome in an autosomal dom inant manner based upon its predicted impact on the protein and absence in contr ols.
Ambry Genetics RCV002431760 SCV002730974 pathogenic Hereditary cancer-predisposing syndrome 2021-12-07 criteria provided, single submitter clinical testing The p.R747* pathogenic mutation (also known as c.2239A>T), located in coding exon 13 of the PMS2 gene, results from an A to T substitution at nucleotide position 2239. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in an individual from colorectal cancer cohort suspicious for Lynch syndrome (Clarke EV et al. Fam Cancer 2019 07;18(3):317-325). 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. RCV003451360 SCV004187693 pathogenic Lynch syndrome 4 2023-09-22 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.
Invitae RCV003758874 SCV004535418 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-08-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg747*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 30729418). ClinVar contains an entry for this variant (Variation ID: 504753). For these reasons, this variant has been classified as Pathogenic.

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