Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825603 | SCV000966946 | likely pathogenic | Lynch syndrome | 2018-03-15 | criteria provided, single submitter | clinical testing | The p.Ser248fs variant in PMS2 has not been previously reported in individuals w ith Lynch syndrome or in large population studies, though the ability of these s tudies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 248 and leads to a premature termination codon 10 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the PMS2 gene is an established disease mechanis m in individuals with Lynch syndrome. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Ser248fs variant is likely pathogenic. ACMG/AMP criteria applied (Richards 2015): PVS1, PM2. |
| Ambry Genetics | RCV001026417 | SCV001188793 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-30 | criteria provided, single submitter | clinical testing | The c.741delT variant, located in coding exon 7 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 741, causing a translational frameshift with a predicted alternate stop codon (p.S248Vfs*10). 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 | RCV002538221 | SCV002965305 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-03-05 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 667013). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 31992580). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser248Valfs*10) 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). |