ATR&RNASEL germline variants: novel findings in a case of familial cancer.

In familial cancer the genetic etiology can play a significant role in the cancer onset. This study aims to explore the genetic predisposition to familial cancer by analysing germline variants in Indian family across generations through whole exome sequencing (WES). Given the limited genetic data from Indian populations and the under representation in the global data, this research seeks to identify genetic variants from India that may contribute to cancer risk. The detection of such constitutional genetic variants in both symptomatic and asymptomatic individuals, can facilitate risk assessment and personalized management strategies for future generations. We report findings from whole exome sequencing for the proband with right breast fibroadenoma and a strong family history of breast cancer, colon cancer and uterine cancer in her mother and maternal grandmother, niece, and paternal grandmother respectively. Sanger sequencing was implemented in the proband and her asymptomatic father to validate the presence of any inherited genetic variants, previously reported in other ethnic groups however being reported for the first time in Indian Population. We report two germline variants ATR c.2320dup and RNASEL c.1029G > A. The variant effect predictor analysis in the proband revealed two pathogenic variants rs1800566 and rs1799983of the NQO3 c.559 C > T (p. Pro187Ser) and NOS3c.894T > G (p. Asp298Glu) genes. The main findings were evaluated for pathogenicity using various mutation score prediction tools, followed by an in-silico analysis of protein structural and functional changes, which revealed alterations in protein domains impacting DNA damage repair and antiviral pathways. Identifying the novel germline variants in the ATR and RNASEL genes within an Indian familial cancer case, underscores the critical role of comprehensive genetic screening in early detection and risk management of hereditary cancers. Our findings emphasize the importance of integrating genomic analyses for personalized medicine approaches, to better assess familial cancer risk and guide early intervention strategies. Our findings will pave the way for functional validation of these variants through in vitro and in vivo studies evaluating RNA and protein expression. We demonstrate importance of expanding genetic studies to diverse populations, which could enhance risk stratification and inform targeted therapeutic developments.