ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1254del (p.Arg419fs)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002419061 SCV002677214 pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing The c.1254delC pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1254, causing a translational frameshift with a predicted alternate stop codon (p.R419Dfs*29). 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. RCV003454205 SCV004187775 pathogenic Lynch syndrome 4 2023-09-20 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV003454205 SCV004205464 likely pathogenic Lynch syndrome 4 2023-09-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003481293 SCV004227150 likely pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing PM2, PVS1
Invitae RCV003594239 SCV004311087 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-08-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg419Aspfs*29) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1761481). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017929 SCV004848588 likely pathogenic Lynch syndrome 2021-11-23 criteria provided, single submitter clinical testing The p.Arg419AspfsX29 variant in PMS2 has not been reported in individuals with PMS2-associated cancers or in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 419 and leads to a premature termination codon 29 amino acids downstream. This alteration is then 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_Supporting.

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