stuff or nonsense?
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.
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