Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164344 | SCV000214977 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-03 | criteria provided, single submitter | clinical testing | The p.P848L variant (also known as c.2543C>T), located in coding exon 15 of the PMS2 gene, results from a C to T substitution at nucleotide position 2543. The proline at codon 848 is replaced by leucine, an amino acid with similar properties. This alteration has been previously reported in a patient with pancreatic cancer (Yang XR et al. Hum. Genet., 2016 Nov;135:1241-1249). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000815392 | SCV000955842 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-20 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 848 of the PMS2 protein (p.Pro848Leu). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with pancreatic cancer (PMID: 27449771). ClinVar contains an entry for this variant (Variation ID: 184993). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731493 | SCV001983513 | uncertain significance | not specified | 2022-04-28 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.2543C>T (p.Pro848Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 202168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2543C>T has been reported in the literature in at least one individual affected with pancreatic cancer (Yang_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Gene |
RCV002291577 | SCV002584194 | uncertain significance | not provided | 2022-10-12 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with pancreatic cancer (Yang et al., 2016); This variant is associated with the following publications: (PMID: Fukui2011[Chapter], 18619468, 27449771) |
| Baylor Genetics | RCV003462131 | SCV004207833 | uncertain significance | Lynch syndrome 4 | 2023-05-21 | criteria provided, single submitter | clinical testing |