Familial cancer with BRCA2 and other germline variants: A case report

Abstract

High-resolution genomic studies can help understanding the predisposition to cancer by identifying constitutional genetic variants of differential penetrance and pathogenicity in a family. We present a case report of whole exome analysis in a case (62/Female) with a history of pancreatic, intestinal, and prostate cancers in the paternal side and her unaffected son from Gujarat, India. Proband showed germline alterations in BRCA2 and NOS3 genes and in NTHL1 gene in her son. BRCA2 c.8954-3C > G has conflicting interpretations being characterized as likely pathogenic and variant of unknown significance (VUS) in 2018 and 2021, while our findings in 2022 classifies it as likely pathogenic. Novel germline genetic variants NOS3 c.1246_1255del (p. Ile417Thrfster9) and NTHL1 c.374dup (p. Val127GlyfsTer43) have been classified as VUS. In-silico analysis of the BRCA2 c.8954-3C > G indicates the location of the genetic variant at the splice site. Proband and her son show co-segregation of 9 constitutional genetic variants; 8 are likely benign and one is benign according to ClinVar. Identification of germline variants and studies on functional evidence will facilitate curated genetic counselling for the family and focussed risk-reduction strategies.