Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000567806 | SCV000663461 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-06 | criteria provided, single submitter | clinical testing | The p.P241A variant (also known as c.721C>G), located in coding exon 7 of the PMS2 gene, results from a C to G substitution at nucleotide position 721. The proline at codon 241 is replaced by alanine, an amino acid with highly similar properties. This variant was not detected in 1,292 biliary tract cancer cases but was seen with with a carrier frequency of 0.001 in 37,583 controls without a personal nor family history of cancer (Okawa Y et al. J Hepatol, 2023 Feb;78:333-342). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001205274 | SCV001376518 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-03-12 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 480307). 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. 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 not expected to disrupt PMS2 protein function. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 241 of the PMS2 protein (p.Pro241Ala). |
| All of Us Research Program, |
RCV004000890 | SCV004833690 | uncertain significance | Lynch syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with alanine at codon 241 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |