ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.535A>T (p.Lys179Ter)

dbSNP: rs1554303861
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574316 SCV000664905 pathogenic Hereditary cancer-predisposing syndrome 2022-01-11 criteria provided, single submitter clinical testing The p.K179* pathogenic mutation (also known as c.535A>T), located in coding exon 5 of the PMS2 gene, results from an A to T substitution at nucleotide position 535. This changes the amino acid from a lysine to a stop codon within coding exon 5. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. RCV003451235 SCV004187728 pathogenic Lynch syndrome 4 2023-09-19 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017678 SCV004848383 likely pathogenic Lynch syndrome 2020-05-13 criteria provided, single submitter clinical testing The p.Lys179X variant in PMS2 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies, but has been reported in ClinVar (Variation ID 480938). This nonsense variant leads to a premature termination codon at position 179, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2.

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