Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000215049 | SCV000274188 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-29 | criteria provided, single submitter | clinical testing | The p.E77K variant (also known as c.229G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 229. The glutamic acid at codon 77 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other 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 | RCV000463790 | SCV000552070 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 77 of the PMS2 protein (p.Glu77Lys). This variant is present in population databases (rs751235177, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 230591). 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. |
Counsyl | RCV000662890 | SCV000785804 | uncertain significance | Lynch syndrome 4 | 2017-12-05 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001547436 | SCV001767141 | uncertain significance | not provided | 2022-07-07 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484) |
Sema4, |
RCV000215049 | SCV002530283 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-15 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV000662890 | SCV004019813 | uncertain significance | Lynch syndrome 4 | 2023-04-04 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Center for Genomic Medicine, |
RCV003320609 | SCV004025135 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000215049 | SCV004359702 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-08 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 77 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. In a large breast cancer case-control study, this variant has been reported in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250862 chromosomes 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. |