Identification of a Novel Mutation in Hereditary Breast Cancerin a Family with Wide Spectrum of Atypical Malignancies

Abstract

Due to phenotypic variability, age-related penetrance, and variety of targeted organs, many families with an inheritedcancer syndrome will not meet syndrome-specific criteria. We report hereditary breast cancer case in a family withgastric cancer, pancreatic cancer, lung sarcoma and penile cancer, suggesting several alternative hereditary cancersyndromes. Mutation screening by NGS was performed using three panels with BRCA1, BRCA2, TP53, BMPR1A, SMAD4, CDH1,STK11, PTEN genes and 409 genes from Ion AmpliSeq Comprehensive Cancer Panel.In maternal lineage we found a novel mutation c.5193_5194del:p.H1731fs in BRCA2 resulted in HBOC. 7 of 8 tested fam ily members (87.5%) were carriers of the mutation; 4 would have been expected from mendelian ratio of 50%. In orderto find out whether the paternal lineage could have another hereditary cancer syndrome we tested paternal uncle withpenile carcinoma. 409 gene panel revealed no pathogenic mutations. VUS’s identified in this study cannot be used tomake clinical decisions.A positive cancer family history in itself is usually not enough to diagnose a cancer syndrome, especially when com mon type cancers are involved. Chance alone may cause the clustering of cancer (especially in large families) and thenumber of possible unaffected relatives.