Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000694654 | SCV000823111 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-08-03 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Glu705 amino acid residue in PMS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16619239, 18602922, 23012243, 26110232, 26318770, 26845104, 27601186). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 573081). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 705 of the PMS2 protein (p.Glu705Asp). 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 constitutional mismatch repair deficiency syndrome (PMID: 32369273). |
| Ambry Genetics | RCV002422521 | SCV002726007 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-01-19 | criteria provided, single submitter | clinical testing | The p.E705D variant (also known as c.2115G>C), located in coding exon 12 of the PMS2 gene, results from a G to C substitution at nucleotide position 2115. The glutamic acid at codon 705 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been identified in a probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome. The individual was diagnosed with breast cancer at age 32 (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Structural analysis demonstrated that this variant is strongly destabilizing to the C-terminal domain of PMS2 and disrupts a highly conserved and functionally important zinc-binding motif (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Department of Pathology and Laboratory Medicine, |
RCV001354123 | SCV001548662 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The PMS2 p.Glu705Asp variant was not identified in the literature nor was it identified in dbSNP, ClinVar, Clinvitae, GeneInsight-COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database databases. The variant was also not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu705 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest this variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |