Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000572720 | SCV000676184 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-22 | criteria provided, single submitter | clinical testing | The p.H532R variant (also known as c.1595A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1595. The histidine at codon 532 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in cohort of 711 Russian breast cancer patients (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000630016 | SCV000750972 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 532 of the PMS2 protein (p.His532Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 486936). 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 with a negative predictive value of 80%. 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. |
Color Diagnostics, |
RCV000572720 | SCV001359491 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with arginine at codon 532 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial cancer (Color internal data) and an individual affected with breast cancer (PMID: 32547938). 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. |
Gene |
RCV003126827 | SCV003803465 | uncertain significance | not provided | 2023-02-09 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and/or family history of breast cancer (Nikitin et al., 2020); This variant is associated with the following publications: (PMID: 32547938) |