[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-379251-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-379251-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","a-case-study-on-ppm1d-and-9-other-shared-germline-alterations-in-a-family","A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family","","Background: High-throughput genotyping enables identification of rare germline variants with different pathogenicity and penetrance, clarifying their roles in cancer predisposition. Methods: NGS-WES was performed on a lung cancer patient with multigenerational family history of tongue, lung, brain, cervical, urothelial, and esophageal cancers, with validation via data mining. Protein structure modeling used I-TASSER, RasMol, and PyMOL. Results: NGS-WES revealed PPM1D c.1654C>T (p.Arg552Ter) as a VUS; three unaffected siblings lacked pathogenic variants, while nine shared variants were benign per ClinVar. Conclusion: PPM1D constitutional alterations are rare, potentially linked to tumor suppressor regulation of the P53 pathway and DNA damage response.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/a-case-study-on-ppm1d-and-9-other-shared-germline-alterations-in-a-family/379251/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/a-case-study-on-ppm1d-and-9-other-shared-germline-alterations-in-a-family/379251.png","ImageObject",300,407,{"name":42,"@type":43},"Terk","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What was the main aim of the study?","Question",{"text":63,"@type":64},"To investigate rare germline genetic alterations in a family with a history of multiple cancers, using NGS-WES and validation strategies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which genetic mutation was identified in the lung cancer patient?",{"text":68,"@type":64},"The study reported a PPM1D c.1654C>T (p.Arg552Ter) mutation in hotspot exon 6, leading to sudden protein truncation and loss of the C-terminal region.",{"name":70,"@type":61,"acceptedAnswer":71},"How were variants interpreted for the unaffected siblings?",{"text":72,"@type":64},"The three unaffected siblings did not show pathogenic variants; comparative analysis identified nine shared variants that were classified as benign according to ClinVar.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},379251,1790458088,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":97,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145},1099525198933,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","RESEARCH ARTICLE  \nEditorial Process: Submission:03/13/2023 Acceptance:06/16/2023  \nA Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family  \nShristi Biswas1, Swati Manekar2, Sonal Rajiv Bakshi1 *  \nAbstract  \nBackground: The use of high-throughput genotyping techniques has enabled us to identify the rare germline genetic variants with different pathogenicity and penetrance, and understand their role in cancer predisposition. We report here a familial cancer case, a study from Western Indian. Methods: NGS-WES was carried out in a lung cancer patient who has a family history of multiple cancers across generations, including tongue, lung, brain, cervical, urothelial, and esophageal cancer. The results were validated by data mining from available data bases. I-TASSER, RasMol and PyMol were used for protein structure modelling. Results: The sequencing byNGS-WES revealed PPM1D c.1654C>T (p.Arg552Ter) mutation in hotspot region exon 6 leading to sudden protein truncation and loss of the C-terminal, due to the substitution of C>T. This mutation was classified as a variant of uncertain significance (VUS), due to limited data on lung cancer, The three unaffected siblings of proband did not show any pathogenic variants and comparative analysis of the four siblings indicate 9 shared genetic variants, classified as benign as per ClinVar. Conclusion: PPM1D constitutional genetic alterations are rare and uncommon in different ethnic populations. This gene encodes a phosphatase playing role in regulating the P53 tumor suppressor pathway and DNA damage response. Genetic alterations in the PPM1D gene maybe linked to history of gliomas, breast cancer, and ovarian cancer onset in the proband’s family.  \nKeywords: ClinVar-whole-exome sequencing-glioma-lung cancer-I-TASSER  \nAsian Pac J Cancer Prev, 24 (6), 2129-2133  \nIntroduction  \nFamilial cancers are an outcome of interaction between environmental factors and genetic makeup, of an individual. The constitutional genetic variants which play role in rare diseases have high penetrance and low allelic frequency for e.g., RAD50 and PPM1D mutations have 0.0003% and 0.003% of allelic frequency which play role in breast, ovarian, brain and lung cancers. The detection of such important rare genetic variants can be missed when the targeted gene panel is only used.  \nThis constraint has been overcome with the use of NGS-WES, enabling the study of rare variants broadly across human exomes, for e.g., reports from Southern India indicate role of CHEK2 in addition to BRCA1, BRCA2 in early onset of HBOC (Hereditary Breast and Ovarian cancer) and lung cancer in families with a history of breast and ovarian cancer (Rajkumar, 2003), while genetic alterations in the MRE11A (p.Arg364Ter) are reported in breast cancer without the BRCA1 and BRCA2 mutations (Bhai, 2017) . NGS-WES in breast cancer patient revealed three recurrent mutations L719fs, K994fs, H1269fs in RAD50 gene, reduce the chances of recurrence free survival (Fan, 2018) .  \nOur earlier study involved NGS-WES in a patient  \nwith breast and ovarian cancer and her asymptomatic son, with a family history of pancreatic, prostate, and intestinal cancer across the generations. Reports showed BRCA2, NOS3 and NTHL1 genetic mutations. In this study wereport a PPM1D heterozygous mutation in the exon 6 of a lung cancer patient. We also report 9 other shared genetic variants in the patient and his three asymptomatic siblings.  \nMaterials and Methods  \nInformed consent of the participants was taken and 6 ml of venous blood was collected in an EDTA vial aseptically, stored at-20ºC. DNA isolation was performed using Qiagen Blood MidikitTM. NGS-WES was done with Exome capture kit. The libraries were sequenced 80-100x coverage on the Illumina sequencing platform to generate paired-end output.  \nClinical details and pedigree  \nWe report a WES study in a lung cancer patient 66Y/M (DM_01). The pedigree in Figure I shows family history tongue, lung, brain, ","cbCaisQ3X1LFWv6N","https://ap.wps.com/l/cbCaisQ3X1LFWv6N","pdf",619591,"English","# Abstract\n# Introduction\n# Materials and Methods\n## Clinical details and pedigree\n## Bioinformatic analysis with GATK Sentieon and GATK4\n## Open source database and in-silico tools used for validation of results and protein modelling","[{\"question\":\"What was the main aim of the study?\",\"answer\":\"To investigate rare germline genetic alterations in a family with a history of multiple cancers, using NGS-WES and validation strategies.\"},{\"question\":\"Which genetic mutation was identified in the lung cancer patient?\",\"answer\":\"The study reported a PPM1D c.1654C\\u003eT (p.Arg552Ter) mutation in hotspot exon 6, leading to sudden protein truncation and loss of the C-terminal region.\"},{\"question\":\"How were variants interpreted for the unaffected siblings?\",\"answer\":\"The three unaffected siblings did not show pathogenic variants; comparative analysis identified nine shared variants that were classified as benign according to ClinVar.\"}]","A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family | PDF",1790234747,13]