Abstract
Germline variants that affect the proofreading activity of polymerases epsilon (POLE) and delta (POLD1) predispose to colorectal adenomas and carcinomas, among other cancers. All cancer-associated pathogenic variants reported to date consist of non-disruptive genetic changes affecting the sequence that codifies the exonuclease domain (ED). Generally, disruptive (frameshift, stop-gain) POLE and POLD1 variants and missense variants outside the ED do not predispose to cancer. However, this statement may not be true for some, very specific variants that would indirectly affect the proofreading activity of the corresponding polymerase. We evaluated, by using multiple approaches, the possibility that POLD1 c.883G>A; p.(Val295Met), -a variant located 9 amino acids upstream the ED and present in ~0.25% of hereditary cancer patients-, affects POLD1 proofreading activity. Our findings show cumulative evidence that support no alteration of the proofreading activity and lack of association with cancer. The variant is classified as likely benign according to the ACMG/AMP guidelines.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16:71–81.
Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136–44.
Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian AQ, Wu Y. et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94–101.
Mur P, Palles C, Tomlinson I, Valle L. Reply to: “Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient”. J Hum Genet. 2020;65:513–4.
Mur P, García-Mulero S, Del Valle J, Magraner-Pardo L, Vidal A, Pineda M, et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020;22:2089–100.
Esteban-Jurado C, Gimenez-Zaragoza D, Munoz J, Franch-Exposito S, Alvarez-Barona M, Ocana T, et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget. 2017;8:26732–43.
Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2016;18:325–32.
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978–80.
Sanz-Pamplona R, Lopez-Doriga A, Paré-Brunet L, Lázaro K, Bellido F, Alonso MH, et al. Exome sequencing reveals AMER1 as a frequently mutated gene in colorectal cancer. Clin Cancer Res. 2015;21:4709–18.
Barbari SR, Kane DP, Moore EA, Shcherbakova PV. Functional analysis of cancer-associated DNA polymerase ε variants in saccharomyces cerevisiae. G3 (Bethesda) 2018;8:1019–29.
Hamzaoui N, Alarcon F, Leulliot N, Guimbaud R, Buecher B, Colas C, et al. Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction. Genet Med. 2020;2:1533–41.
Castaño-Vinyals G, Aragonés N, Pérez-Gómez B, Martín V, Llorca J, Moreno V, et al. Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design. Gac Sanit. 2015;29:308–15.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Funding
This work was funded by the Spanish Ministry of Science and Innovation, co-funded by FEDER funds [SAF2016-80888-R, PID2019-111254RB-I00, Severo Ochoa SVP-2014-068895 contract (LM-P)]; Instituto de Salud Carlos III, co-funded by FEDER funds [CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract (PM) and PI19/00553, CIBERONC ayuda iniciación a la investigación (EE)]; EMBO Short-Term Fellowship [8374 (LM-P)]; Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Mur, P., Magraner-Pardo, L., García-Mulero, S. et al. Solving the enigma of POLD1 p.V295M as a potential cause of increased cancer risk. Eur J Hum Genet 30, 485–489 (2022). https://doi.org/10.1038/s41431-021-00926-6
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41431-021-00926-6
This article is cited by
-
No April fools in clinical genomics
European Journal of Human Genetics (2022)
