A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family

Document Type : Research Articles


1 Institute of Science, Nirma University, Ahmadabad, Gujarat India.

2 Institute of Technology, Nirma University, Gujarat India.


Background: 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 by NGS-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.


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