ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.780del (p.Asp261fs)

dbSNP: rs587779344
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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) RCV000076886 SCV000108382 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000076886 SCV000731683 pathogenic Lynch syndrome 2017-07-07 criteria provided, single submitter clinical testing The p.Asp261fs variant in PMS2 has been identified as a germline variant in 1 in dividual with Lynch syndrome (with PMS2-negative colorectal cancer; Borras 2013) and was absent from large population studies. This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 261 and leads to a premature termination codon 46 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PMS2 gene is an established disease mechanism fo r Lynch syndrome. Additionally, this variant was classified as Pathogenic on Sep tember 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV00010838 2.2). In summary, the p.Asp261fs variant meets criteria to be classified as path ogenic for Lynch syndrome in an autosomal dominant manner.
Ambry Genetics RCV002408600 SCV002670744 pathogenic Hereditary cancer-predisposing syndrome 2021-09-07 criteria provided, single submitter clinical testing The c.780delC pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 780, causing a translational frameshift with a predicted alternate stop codon (p.D261Mfs*46). This alteration has been identified in a female diagnosed with MSI-high colorectal cancer at age 48; this tumor showed loss of PMS2 on immunohistochemistry (Borràs E et al. J. Med. Genet., 2013 Aug;50:552-63). 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 RCV003593906 SCV004294445 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp261Metfs*46) 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 premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 23709753). ClinVar contains an entry for this variant (Variation ID: 91367). For these reasons, this variant has been classified as Pathogenic.

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