PT  - JOURNAL ARTICLE
AU  - J E Higgs
AU  - E F Harkness
AU  - N L Bowers
AU  - E Howard
AU  - A J Wallace
AU  - F Lalloo
AU  - W G Newman
AU  - D G Evans
TI  - The <em>BRCA2</em> polymorphic stop codon: stuff or nonsense?
AID  - 10.1136/jmedgenet-2015-103206
DP  - 2015 Sep 01
TA  - Journal of Medical Genetics
PG  - 642--645
VI  - 52
IP  - 9
4099  - http://jmg.bmj.com/content/52/9/642.short
4100  - http://jmg.bmj.com/content/52/9/642.full
SO  - J Med Genet2015 Sep 01; 52
AB  - Background Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer.Methods We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations.Results We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis.Conclusions It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT.