Females with biallelic germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with biallelic gPVs ( = 291). In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- ( = 19), thyroid- ( = 19), and prostate (pre)malignancies ( = 12). Females with biallelic loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. Our study suggests that biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with biallelic gPVs is missed as diagnostic testing for often is limited to individuals who developed breast cancer.

中文翻译：

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CHEK2 中具有双等位基因种系致病性变异的个体的异质癌症表型

与具有单等位基因 gPV 的个体相比，具有双等位基因种系致病变异 (gPV) 的女性更容易患多种乳腺癌。这项研究旨在扩大对其他恶性肿瘤发生的认识。对患有多种原发性恶性肿瘤的个体进行外显子组测序，发现 3 名个体的 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) 功能丧失 gPV 处于双等位基因状态。我们收集了另一组具有双等位基因 gPV 的个体的表型 (= 291)。总共有 157 人（53.4%；157/294 人）患有 ≥1 种（前期）恶性肿瘤。除乳腺癌之外，最常见的（前期）恶性肿瘤是结直肠癌（= 19）、甲状腺（= 19）和前列腺（前期）恶性肿瘤（= 12）。与 c.470T>C p.(Ile157Thr) 错义变体的双等位基因女性相比，具有双等位基因 gPV 功能丧失的女性更容易患 ≥2 种（前）恶性肿瘤，且年龄更早。此外，26 名具有双等位基因 gPV 的男性（31%；26/84 男性）患有 15 种起源的 ≥1 种（前期）恶性肿瘤。我们的研究表明，双等位基因 gPV 可能会增加女性和男性各种组织中多种恶性肿瘤的易感性。然而，由于诊断测试通常仅限于患乳腺癌的个体，因此很大一部分具有双等位基因 gPV 的个体可能会被遗漏。