Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
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, |
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. |