Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000657086 | SCV000289291 | likely benign | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000657086 | SCV000293515 | uncertain significance | not provided | 2018-11-19 | criteria provided, single submitter | clinical testing | This variant is denoted POLE c.2171C>T at the cDNA level, p.Ala724Val (A724V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been reported in at least one individual with breast cancer (Dominguez-Valentin 2018). POLE Ala724Val was observed at an allele frequency of 0.06% (68/114,056) in individuals of European ancestry in large population cohorts (Lek 2016). POLE Ala724Val is located in the polymerase domain (Preston 2010). While protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, multiple splicing models predict that this variant may create a cryptic splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether POLE Ala724Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Ambry Genetics | RCV000575275 | SCV000671257 | likely benign | Hereditary cancer-predisposing syndrome | 2024-02-27 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Mendelics | RCV000709268 | SCV000838699 | uncertain significance | Familial colorectal cancer | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000657086 | SCV000888509 | uncertain significance | not provided | 2019-05-07 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001818624 | SCV002066319 | uncertain significance | not specified | 2021-01-08 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the POLE gene demonstrated a sequence change, c.2171C>T, in exon 19 that results in an amino acid change, p.Ala724Val. This sequence change has been described in the gnomAD database with a frequency of 0.063% in the European population (dbSNP rs61734163). The p.Ala724Val change has been identified in two BRCA1 and BRCA2 negative individuals with breast or gynecologic cancer (PMID: 29371908). The p.Ala724Val change affects a moderately conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala724Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala724Val change remains unknown at this time. |
Sema4, |
RCV000575275 | SCV002536779 | benign | Hereditary cancer-predisposing syndrome | 2021-02-07 | criteria provided, single submitter | curation | |
St. |
RCV000233305 | SCV003842982 | uncertain significance | Colorectal cancer, susceptibility to, 12 | 2023-01-09 | criteria provided, single submitter | clinical testing | The POLE c.2171C>T (p.Ala724Val) missense change has a maximum subpopulation frequency of 0.063% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.? |
Center for Genomic Medicine, |
RCV001818624 | SCV005089975 | uncertain significance | not specified | 2024-07-31 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004532922 | SCV004740723 | uncertain significance | POLE-related disorder | 2023-11-11 | no assertion criteria provided | clinical testing | The POLE c.2171C>T variant is predicted to result in the amino acid substitution p.Ala724Val. This variant has been reported in individuals with breast and/or gynecological cancer (Table 2, Patient ID 5378, Dominguez-Valentin et al. 2018. PubMed ID: 29371908; Table S1, McDonald et al. 2022. PubMed ID: 36315513). It has also been reported in an individual with thyroid cancer that harbored a variant in another gene (Table 2, Mio et al. 2021. PubMed ID: 33821390). This variant is reported in 0.063% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133244944-G-A) and has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240427/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |