Comprehensive bioinformatics analysis of selected germline variants of uncertain significance identified in a cohort of Sri Lankan hereditary breast cancer patients.
| Title: | Comprehensive bioinformatics analysis of selected germline variants of uncertain significance identified in a cohort of Sri Lankan hereditary breast cancer patients. |
|---|---|
| Authors: | Arachchige NDS; Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo 03, Sri Lanka.; Sirisena ND; Department of Anatomy, Genetics and Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka. nirmala@anat.cmb.ac.lk.; De Silva S; Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo 03, Sri Lanka.; Senathilake KS; Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo 03, Sri Lanka.; Faizan M; Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo 03, Sri Lanka.; Dissanayake VHW; Department of Anatomy, Genetics and Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka. |
| Source: | Human genomics [Hum Genomics] 2025 Feb 12; Vol. 19 (1), pp. 12. Date of Electronic Publication: 2025 Feb 12. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101202210 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-7364 (Electronic) Linking ISSN: 14739542 NLM ISO Abbreviation: Hum Genomics Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2012- : London : BioMed Central; Original Publication: London : Henry Stewart Publications, c2003- |
| MeSH Terms: | Germ-Line Mutation*/genetics ; Computational Biology*/methods ; Breast Neoplasms*/genetics ; Breast Neoplasms*/pathology ; Breast Neoplasms*/epidemiology ; Genetic Predisposition to Disease*; Sri Lanka/epidemiology ; BRCA1 Protein/genetics ; Checkpoint Kinase 2/genetics ; BRCA2 Protein/genetics ; RNA Helicases/genetics ; Fanconi Anemia Complementation Group N Protein/genetics ; Fanconi Anemia Complementation Group Proteins/genetics ; Humans ; Female ; High-Throughput Nucleotide Sequencing ; Adult ; Middle Aged ; Cohort Studies |
| Abstract: | Background: Next-generation sequencing (NGS)-based testing is a cost-effective method for identifying pathogenic germline genetic variations in cancer-predisposing genes in hereditary breast cancer. However, many of the variants detected through NGS are classified as variants of uncertain significance (VUS), where the impact of the variants on protein function remains unclear. Bioinformatics analysis using multiple computational tools is postulated to aid in generating new knowledge regarding the functional relevance of these VUS. This study aimed to gain new insights into the potential pathogenicity of a selected set of VUS identified in a cohort of Sri Lankan hereditary breast cancer patients using advanced bioinformatics tools.; Methods: The cancer database at the Centre for Genetics and Genomics contains genomic and clinical data from patients who had undergone germline genetic testing between 2015 and 2023. Five germline VUS detected in breast cancer affected patients were identified from the existing database and selected for further bioinformatics analysis using a combination of in-silico pathogenicity prediction tools, 3D protein modeling with structural analysis, and protein structural stability assessment with molecular dynamic simulation (MDS). The VUS included: BRCA1:(NM_007294.4):c.3392A > G;p.Asp1131Gly, (rs1555587813); BRIP1:(NM_032043.3):c.3103C > T;p.Arg1035Cys, (rs45437094); CHEK2:(NM_007194.4):c.60G > T;p.Gln20His, (rs375507194); MET:(NM_000245.4):c.840G > T;p.Arg280Ser, (rs1207381066); and STK11:(NM_000455.5):c.355A > G;p.Asn119Asp, (rs545015076).; Results: Two variants MET:(NM_000245.4):c.840G > T;p.Arg280Ser and BRCA1:(NM_007294.4):c.3392A > G; p.Asp1131Gly are predicted to have high-risk potential for causing significant impacts on the protein structure and function. Align GVGD results and the MDS data for the BRIP1:(NM_032043.3):c.3103C > T;p.Arg1035Cys variant suggested some alterations that require further confirmation. The CHEK2:(NM_007194.4):c.60G > T;p.Gln20His variant suggested an intermediate impact, whereas STK11:(NM_000455.5):c.355A > G;p.Asn119Asp suggested no significant structural or functional impact on the protein.; Conclusions: This study contributes valuable insights into the potential structural and functional implications of five VUS in cancer predisposition genes. Our results suggest a high-risk potential for variants in MET, BRCA1 and BRIP1, warranting further investigation to delineate their exact biological effects and to better understand their role in breast cancer risk.; (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: Ethical approval for the study was obtained from the Ethics Review Committee, Faculty of Medicine, University of Colombo [EC-22-141]. Prior written informed consent had been obtained from the participants for the use of these genomic data for future research studies. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
| References: | Breast Cancer Res. 2020 May 11;22(1):43. (PMID: 32393398); Oncotarget. 2017 Sep 11;8(44):76722-76739. (PMID: 29100344); J Mol Biol. 2022 Jun 15;434(11):167567. (PMID: 35662467); Br J Radiol. 2022 Feb 1;95(1130):20211033. (PMID: 34905391); Genet Med. 2015 May;17(5):405-24. (PMID: 25741868); Bioinformatics. 2006 Jan 15;22(2):195-201. (PMID: 16301204); Biochem J. 2021 Sep 30;478(18):3467-3483. (PMID: 34591954); Nature. 1984 Sep 6-11;311(5981):29-33. (PMID: 6590967); J Mol Liq. 2022 May 15;354:118901. (PMID: 35309259); Biomark Med. 2014;8(4):589-603. (PMID: 24796624); Nat Rev Cancer. 2002 Apr;2(4):289-300. (PMID: 12001990); Life (Basel). 2022 Jul 09;12(7):. (PMID: 35888106); J Med Genet. 2021 Aug;58(8):565-569. (PMID: 32467295); Genet Med. 2020 May;22(5):825-830. (PMID: 31911673); Proteins. 2003;53 Suppl 6:352-68. (PMID: 14579324); Cell Death Dis. 2017 Dec 13;8(12):3210. (PMID: 29238047); Protein Sci. 2021 Jan;30(1):60-69. (PMID: 32881105); Int J Mol Epidemiol Genet. 2013 Jun 25;4(2):77-85. (PMID: 23875061); Front Mol Neurosci. 2022 Oct 28;15:1026530. (PMID: 36385762); PLoS One. 2024 Jun 21;19(6):e0298092. (PMID: 38905172); Int J Mol Sci. 2021 Oct 20;22(21):. (PMID: 34768775); Front Genet. 2023 Feb 21;14:1052383. (PMID: 36896237); BMC Res Notes. 2023 Jun 5;16(1):95. (PMID: 37277882); J Biomed Biotechnol. 2011;2011:165214. (PMID: 21687596); Nat Rev Drug Discov. 2008 Jun;7(6):504-16. (PMID: 18511928) |
| Contributed Indexing: | Keywords: Bioinformatics; Breast cancer; Genomics; Next-generation sequencing; Protein modeling; VUS |
| Substance Nomenclature: | 0 (BRCA1 Protein); 0 (BRCA1 protein, human); EC 3.6.4.13 (BRIP1 protein, human); EC 2.7.1.11 (Checkpoint Kinase 2); 0 (BRCA2 Protein); EC 2.7.11.1 (CHEK2 protein, human); EC 3.6.4.13 (RNA Helicases); 0 (Fanconi Anemia Complementation Group N Protein); 0 (Fanconi Anemia Complementation Group Proteins) |
| SCR Disease Name: | Breast Cancer, Familial |
| Entry Date(s): | Date Created: 20250212 Date Completed: 20250507 Latest Revision: 20250507 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11823233 |
| DOI: | 10.1186/s40246-024-00703-8 |
| PMID: | 39940038 |
| Database: | MEDLINE |
Journal Article