ATM 和 CHEK2 中的有害种系变异与乳腺癌风险中度增加有关。其他癌症的风险仍不清楚。使用来自英国生物银行的与癌症登记数据（348-488 名参与者）相关的全外显子组序列数据评估了 ATM 和 CHEK2 编码变异的癌症关联，并作为回顾性病例对照和前瞻性分析队列研究。根据癌症类型和基因估计优势比、风险比和组合相对风险 (RR)。对蛋白质截短变异 (PTV) 和罕见错义变异 (rMSV；等位基因频率 <0.1%) 进行了单独分析。ATM 中的 PTV 与九种癌症的风险增加相关，p<0.001（胰腺、食道、肺癌、黑色素瘤、乳腺癌、卵巢癌、前列腺癌、膀胱癌、淋巴性白血病 (LL)），以及 3 个 p<0.05（结肠癌、弥漫性非霍奇金淋巴瘤 (DNHL)、直肠乙状结肠交界处）。 rMSV 携带者患四种癌症的风险增加（p<0.05：胃癌、胰腺癌、前列腺癌、霍奇金病 (HD)）。乳腺癌、前列腺癌以及 rMSV 位于 FAT 或 PIK 域中的任何癌症的 RR 最高，并且组合注释依赖性缺失评分位于最高五分位。CHEK2 中的 PTV 与三种癌症相关，p<0.001（乳腺癌、前列腺癌） ，HD）和 6 个 p<0.05（食道、黑色素瘤、卵巢、肾、DNHL、骨髓性白血病）。 rMSV 携带者患五种癌症的风险增加（p<0.001：乳腺癌、前列腺癌、LL；p<0.05：黑色素瘤、多发性骨髓瘤）。ATM 和 CHEK2 中的 PTV 与多种癌症相关，其中胰腺癌的 RR 最高ATM PTV 携带者患癌症。这些发现可以为携带者的遗传咨询提供信息。© 作者（或其雇主）2024。CC BY 允许重复使用。英国医学杂志出版。

Deleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear.Cancer associations for coding variants in ATM and CHEK2 were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0.1%).PTVs in ATM were associated with increased risks of nine cancers at p<0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin's lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p<0.05: stomach, pancreas, prostate, Hodgkin's disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.PTVs in CHEK2 were associated with three cancers at p<0.001 (breast, prostate, HD) and six at p<0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0.001: breast, prostate, LL; p<0.05: melanoma, multiple myeloma).PTVs in ATM and CHEK2 are associated with a wide range of cancers, with the highest RR for pancreatic cancer in ATM PTV carriers. These findings can inform genetic counselling of carriers.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.