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BackgroundInvasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2, and TP53 in sporadic ILC and LCIS diagnosed in women ages ≤60 years.MethodsAccess Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2, and PALB2 using a custom-made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls.ResultsCase-control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2, and CDH1 in women with ILC. CHEK2 was the only gene that showed an association with pure LCIS [OR = 9.90; 95% confidence interval (CI), 3.42-28.66, P = 1.4 × 10-5] with a larger effect size seen in LCIS compared with ILC (OR = 4.31; 95% CI, 1.61-11.58, P = 1.7 × 10-3).ConclusionsEleven percent of patients with ILC ages ≤40 years carried germline variants in known breast cancer susceptibility genes.ImpactWomen with ILC ages ≤40 years should be offered genetic screening using a panel of genes that includes BRCA2, CHEK2, PALB2, and CDH1.

Original publication




Journal article


Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

Publication Date





1162 - 1168


School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London, United Kingdom.


Humans, Breast Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Germ-Line Mutation, Middle Aged, Female