No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.
Easton DF., Lesueur F., Decker B., Michailidou K., Li J., Allen J., Luccarini C., Pooley KA., Shah M., Bolla MK., Wang Q., Dennis J., Ahmad J., Thompson ER., Damiola F., Pertesi M., Voegele C., Mebirouk N., Robinot N., Durand G., Forey N., Luben RN., Ahmed S., Aittomäki K., Anton-Culver H., Arndt V., Australian Ovarian Cancer Study Group None., Baynes C., Beckman MW., Benitez J., Van Den Berg D., Blot WJ., Bogdanova NV., Bojesen SE., Brenner H., Chang-Claude J., Chia KS., Choi J-Y., Conroy DM., Cox A., Cross SS., Czene K., Darabi H., Devilee P., Eriksson M., Fasching PA., Figueroa J., Flyger H., Fostira F., García-Closas M., Giles GG., Glendon G., González-Neira A., Guénel P., Haiman CA., Hall P., Hart SN., Hartman M., Hooning MJ., Hsiung C-N., Ito H., Jakubowska A., James PA., John EM., Johnson N., Jones M., Kabisch M., Kang D., kConFab Investigators None., Kosma V-M., Kristensen V., Lambrechts D., Li N., Lifepool Investigators None., Lindblom A., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoukian S., Margolin S., Matsuo K., Meindl A., Mitchell G., Muir K., NBCS Investigators None., Nevelsteen I., van den Ouweland A., Peterlongo P., Phuah SY., Pylkäs K., Rowley SM., Sangrajrang S., Schmutzler RK., Shen C-Y., Shu X-O., Southey MC., Surowy H., Swerdlow A., Teo SH., Tollenaar RAEM., Tomlinson I., Torres D., Truong T., Vachon C., Verhoef S., Wong-Brown M., Zheng W., Zheng Y., Nevanlinna H., Scott RJ., Andrulis IL., Wu AH., Hopper JL., Couch FJ., Winqvist R., Burwinkel B., Sawyer EJ., Schmidt MK., Rudolph A., Dörk T., Brauch H., Hamann U., Neuhausen SL., Milne RL., Fletcher O., Pharoah PDP., Campbell IG., Dunning AM., Le Calvez-Kelm F., Goldgar DE., Tavtigian SV., Chenevix-Trench G.
BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.