The BRCA2 polymorphic stop codon: stuff or nonsense?

BackgroundDespite 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.MethodsWe have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRC...

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Published in:Journal of medical genetics Vol. 52; no. 9; pp. 642 - 645
Main Authors: Higgs, J E, Harkness, E F, Bowers, N L, Howard, E, Wallace, A J, Lalloo, F, Newman, W G, Evans, D G
Format: Journal Article
Language:English
Published: England BMJ Publishing Group LTD 01.09.2015
Subjects:
Breast cancer
Breast Neoplasms - genetics
Codon, Terminator
Esophageal cancer
Esophageal Neoplasms - genetics
Europe
Female
Frameshift Mutation
Genes, BRCA2
Genetic Predisposition to Disease
Humans
Lung cancer
Lung Neoplasms - genetics
Male
Mutation
Ovarian cancer
Pancreatic cancer
Pancreatic Neoplasms - genetics
Polymorphism, Single Nucleotide
Risk assessment
Europe
England
United Kingdom > UK
Germany
Finland
Cancer: oesophageal
BRCA2 polymorphic stop codon
Cancer: breast
Cancer: pancreatic
Cancer: lung
ISSN:0022-2593, 1468-6244
Online Access:Get full text
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Summary:BackgroundDespite 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.MethodsWe 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.ResultsWe 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.ConclusionsIt 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.
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ISSN:0022-2593
1468-6244
DOI:10.1136/jmedgenet-2015-103206