Pathogenic TP53 germline variants cause young-onset breast cancer and other cancers of the Li-Fraumeni syndrome (LFS) spectrum, but the clinical consequences of partial-loss-of function TP53 variants are incompletely understood. In the consecutive cohort of Palestinian breast cancer patients of the Middle East Breast Cancer Study (MEBCS), breast cancer risk among TP53 p. R181C heterozygotes was 50% by age 50 y and 81% by age 80 y. In contrast, prevalence of pediatric cancers in the MEBCS was similar among first degree relatives of TP53 p. R181C carriers (3/519 = 0.0058) and first degree relatives of MEBCS patients with no pathogenic germline variant in any known breast cancer gene (7/1082 = 0.0065; OR = 0.90, 95%CI [0.23,3.49], Fisher P = .90 (2-tailed)). This result suggests that in families harboring this TP53 allele, genetic testing in children is unwarranted, and screening children for LFS tumors is unnecessary. More generally, some TP53 missense alleles can predispose to very high risk of breast cancer without pleiotropic effects.

中文翻译：

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TP53 错义等位基因易患乳腺癌高危，但非儿科癌症


致病性 TP53 种系变异可导致早发性乳腺癌和 Li-Fraumeni 综合征 （LFS） 谱系的其他癌症，但部分功能丧失 TP53 变异的临床后果尚不完全清楚。在中东乳腺癌研究 （MEBCS） 的巴勒斯坦乳腺癌患者连续队列中，TP53 p.R181C 杂合子在 50 岁时为 50%，在 80 岁时为 81%。相比之下，MEBCS 中儿科癌症的患病率在 TP53 p 的一级亲属中相似。R181C 携带者 （3/519 = 0.0058） 和 MEBCS 患者的一级亲属，在任何已知的乳腺癌基因中没有致病性种系变异 （7/1082 = 0.0065;OR = 0.90， 95%CI [0.23,3.49]，Fisher P = .90 （2-tailed））。这一结果表明，在携带这种 TP53 等位基因的家庭中，对儿童进行基因检测是没有必要的，并且没有必要筛查儿童的 LFS 肿瘤。更一般地说，一些 TP53 错义等位基因可导致乳腺癌的极高风险，而没有多效性作用。