{"doi":"10.1002/ijc.70070","title":"Genetic landscape of Pakistani familial breast cancer patients using multigene panel testing","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Pathogenic/likely pathogenic (P/LP) variants in high‐, moderate‐, and low‐penetrance genes account for approximately half of all familial breast cancer (BC) cases. In Pakistan, data on P/LP variants beyond\n                    <jats:italic>BRCA1/2</jats:italic>\n                    remain limited. This study investigated the frequency and distribution of P/LP variants in Pakistani familial BC patients using a 14‐gene hereditary breast and ovarian cancer (HBOC) core panel. A total of 160 familial BC patients previously tested negative for protein‐truncating variants in\n                    <jats:italic>BRCA1</jats:italic>\n                    ,\n                    <jats:italic>BRCA2</jats:italic>\n                    ,\n                    <jats:italic>CHEK2</jats:italic>\n                    ,\n                    <jats:italic>PALB2</jats:italic>\n                    ,\n                    <jats:italic>RAD51C</jats:italic>\n                    ,\n                    <jats:italic>RAD51D</jats:italic>\n                    , and\n                    <jats:italic>TP53</jats:italic>\n                    using conventional methods were included. Next‐generation sequencing (NGS) was performed using the Illumina MiSeq platform, and all identified P/LP variants were validated by Sanger sequencing. Twenty‐four unique P/LP variants were identified across seven genes:\n                    <jats:italic>BRCA1</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 10),\n                    <jats:italic>BRCA2</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 6),\n                    <jats:italic>TP53</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 3),\n                    <jats:italic>CHEK2</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 2),\n                    <jats:italic>PALB2</jats:italic>\n                    ,\n                    <jats:italic>ATM</jats:italic>\n                    , and\n                    <jats:italic>RAD51C</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 1 each). Two recurrent\n                    <jats:italic>BRCA1</jats:italic>\n                    variants, p.Gln169Ter and p.Val757Phefs*8, were identified in three patients each. NGS‐detected P/LP variants were identified in 18.1% (29/160) of patients. When combined with previous germline testing in the same cohort, the overall detection rate increased to 50.2% (132/263):\n                    <jats:italic>BRCA1</jats:italic>\n                    (101/263; 38.4%),\n                    <jats:italic>BRCA2</jats:italic>\n                    (22/263; 8.4%),\n                    <jats:italic>TP53</jats:italic>\n                    (3/263; 1.1%),\n                    <jats:italic>CHEK2</jats:italic>\n                    (2/263; 0.8%),\n                    <jats:italic>PALB2</jats:italic>\n                    (2/263; 0.8%),\n                    <jats:italic>ATM</jats:italic>\n                    (1/263; 0.4%) and\n                    <jats:italic>RAD51C</jats:italic>\n                    (1/263; 0.4%). Among these,\n                    <jats:italic>BRCA1/2</jats:italic>\n                    variants accounted for 93.2% (123/132) of all P/LP variants. Our findings demonstrate that P/LP variants are concentrated in a limited number of genes, with\n                    <jats:italic>BRCA1/2</jats:italic>\n                    as the predominant contributors. We propose a cost‐effective, first‐tier genetic testing panel comprising seven genes (\n                    <jats:italic>ATM</jats:italic>\n                    ,\n                    <jats:italic>BRCA1</jats:italic>\n                    ,\n                    <jats:italic>BRCA2</jats:italic>\n                    ,\n                    <jats:italic>CHEK2</jats:italic>\n                    ,\n                    <jats:italic>RAD51C</jats:italic>\n                    ,\n                    <jats:italic>PALB2</jats:italic>\n                    , and\n                    <jats:italic>TP53</jats:italic>\n                    ) for familial BC risk assessment in Pakistan.\n                  </jats:p>","journal":"International Journal of Cancer","year":2025,"id":653694,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":877707,"name":"Noor Muhammad","orcid":"0000-0002-8421-7615","position":1,"is_corresponding":false},{"id":1705641,"name":"Shumaila Arif","orcid":null,"position":2,"is_corresponding":false},{"id":1705642,"name":"Humaira Naeemi","orcid":null,"position":3,"is_corresponding":false},{"id":55329,"name":"Ute Hamann","orcid":"0000-0002-5294-6266","position":4,"is_corresponding":false},{"id":312468,"name":"Muhammad Usman Rashid","orcid":"0000-0002-7684-3122","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Genetic landscape of Pakistani familial breast cancer patients using multigene panel testing","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Pathogenic/likely pathogenic (P/LP) variants in high‐, moderate‐, and low‐penetrance genes account for approximately half of all familial breast cancer (BC) cases. In Pakistan, data on P/LP variants beyond\n                    <jats:italic>BRCA1/2</jats:italic>\n                    remain limited. This study investigated the frequency and distribution of P/LP variants in Pakistani familial BC patients using a 14‐gene hereditary breast and ovarian cancer (HBOC) core panel. A total of 160 familial BC patients previously tested negative for protein‐truncating variants in\n                    <jats:italic>BRCA1</jats:italic>\n                    ,\n                    <jats:italic>BRCA2</jats:italic>\n                    ,\n                    <jats:italic>CHEK2</jats:italic>\n                    ,\n                    <jats:italic>PALB2</jats:italic>\n                    ,\n                    <jats:italic>RAD51C</jats:italic>\n                    ,\n                    <jats:italic>RAD51D</jats:italic>\n                    , and\n                    <jats:italic>TP53</jats:italic>\n                    using conventional methods were included. Next‐generation sequencing (NGS) was performed using the Illumina MiSeq platform, and all identified P/LP variants were validated by Sanger sequencing. Twenty‐four unique P/LP variants were identified across seven genes:\n                    <jats:italic>BRCA1</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 10),\n                    <jats:italic>BRCA2</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 6),\n                    <jats:italic>TP53</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 3),\n                    <jats:italic>CHEK2</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 2),\n                    <jats:italic>PALB2</jats:italic>\n                    ,\n                    <jats:italic>ATM</jats:italic>\n                    , and\n                    <jats:italic>RAD51C</jats:italic>\n                    (\n                    <jats:italic>n</jats:italic>\n                     = 1 each). Two recurrent\n                    <jats:italic>BRCA1</jats:italic>\n                    variants, p.Gln169Ter and p.Val757Phefs*8, were identified in three patients each. NGS‐detected P/LP variants were identified in 18.1% (29/160) of patients. When combined with previous germline testing in the same cohort, the overall detection rate increased to 50.2% (132/263):\n                    <jats:italic>BRCA1</jats:italic>\n                    (101/263; 38.4%),\n                    <jats:italic>BRCA2</jats:italic>\n                    (22/263; 8.4%),\n                    <jats:italic>TP53</jats:italic>\n                    (3/263; 1.1%),\n                    <jats:italic>CHEK2</jats:italic>\n                    (2/263; 0.8%),\n                    <jats:italic>PALB2</jats:italic>\n                    (2/263; 0.8%),\n                    <jats:italic>ATM</jats:italic>\n                    (1/263; 0.4%) and\n                    <jats:italic>RAD51C</jats:italic>\n                    (1/263; 0.4%). Among these,\n                    <jats:italic>BRCA1/2</jats:italic>\n                    variants accounted for 93.2% (123/132) of all P/LP variants. Our findings demonstrate that P/LP variants are concentrated in a limited number of genes, with\n                    <jats:italic>BRCA1/2</jats:italic>\n                    as the predominant contributors. We propose a cost‐effective, first‐tier genetic testing panel comprising seven genes (\n                    <jats:italic>ATM</jats:italic>\n                    ,\n                    <jats:italic>BRCA1</jats:italic>\n                    ,\n                    <jats:italic>BRCA2</jats:italic>\n                    ,\n                    <jats:italic>CHEK2</jats:italic>\n                    ,\n                    <jats:italic>RAD51C</jats:italic>\n                    ,\n                    <jats:italic>PALB2</jats:italic>\n                    , and\n                    <jats:italic>TP53</jats:italic>\n                    ) for familial BC risk assessment in Pakistan.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40749126","pmcid":null,"openalex_id":"https://openalex.org/W4412836649","authors":[],"funders":[],"total_grants":0,"fwci":0.0,"citation_percentile":0.19499534,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.70070","host_type":"publisher"},{"url":"https://doi.org/10.1002/ijc.70070","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40749126","host_type":"repository"}],"fields_of_study":["BRCA gene mutations in cancer","Genetic factors in colorectal cancer","Genomic variations and chromosomal abnormalities","Humans","Female","Pakistan","Breast Neoplasms","Middle Aged","Adult","Genetic Predisposition to Disease","Genetic Testing","High-Throughput Nucleotide Sequencing","Checkpoint Kinase 2","Aged","Fanconi Anemia Complementation Group N Protein","BRCA1 Protein","BRCA2 Protein","Germ-Line Mutation","Breast Cancer, Familial"],"mesh_terms":["Fanconi Anemia Complementation Group N Protein","Adult","Aged","Breast Neoplasms","Female","Genetic Testing","Humans","Middle Aged","Pakistan","Germ-Line Mutation","BRCA1 Protein","Genetic Predisposition to Disease","BRCA2 Protein","High-Throughput Nucleotide Sequencing","Checkpoint Kinase 2"],"keywords":["CHEK2","PALB2","Penetrance","Breast cancer","Sanger sequencing","Germline mutation","Genetics","Medicine","Oncology","Genetic testing","Internal medicine","Cancer","Biology","Gene","Mutation","Phenotype","Pakistan","Familial Breast Cancer","Next‐generation Sequencing","Pathogenic Variants"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T23:54:50.461965Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}