Submissions for variant NM_006231.4(POLE):c.2171C>T (p.Ala724Val)

gnomAD frequency: 0.00040  dbSNP: rs61734163

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657086	SCV000289291	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	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, University of Chicago	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, Sema4	RCV000575275	SCV002536779	benign	Hereditary cancer-predisposing syndrome	2021-02-07	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	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, Rigshospitalet, Copenhagen University Hospital	RCV001818624	SCV005089975	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657086	SCV005877471	uncertain significance	not provided	2024-04-13	criteria provided, single submitter	clinical testing	The POLE c.2171C>T; p.Ala724Val variant (rs61734163; ClinVar Variation ID: 240427) is reported in the literature in several individuals with a personal or family history of cancer, but it has not been demonstrated to be disease-causing (Dominguez-Valentin 2018, Mio 2021, McDonald and Ricks-Santi 2022). This variant is found in the non-Finnish European population with an allele frequency of 0.06% (73/ 116480 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.136). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. PMID: 29371908 McDonald JT and Ricks-Santi LJ. Hereditary variants of unknown significance in African American women with breast cancer. PLoS One. 2022 Oct 31;17(10):e0273835. PMID: 36315513 Mio C et al. Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility. Endocrine. 2021 Sep;73(3):648-657. PMID: 33821390 Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516.
PreventionGenetics, part of Exact Sciences	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.