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Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.
Human Mutation ( IF 3.9 ) Pub Date : 2020-06-02 , DOI: 10.1002/humu.24060
Cristina Fortuno 1 , Jessica Mester 2 , Tina Pesaran 3 , Jeffrey N Weitzel 4 , Jill Dolinsky 3 , Amal Yussuf 3 , Kelly McGoldrick 3 , Judy E Garber 5 , Sharon A Savage 6 , Payal P Khincha 6 , D Gareth Evans 7 , Maria Isabel Achatz 8 , Kim E Nichols 9 , Kara N Maxwell 10 , Joshua D Schiffman 11 , Renata Sandoval 8 , , Paul A James 12 , Amanda B Spurdle 1
Affiliation  

Early onset breast cancer is the most common malignancy in women with Li‐Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53‐specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.

中文翻译:

建议在 ACMG/AMP 指南中将 HER2+ 乳腺肿瘤表型用于种系 TP53 变异分类。

早发性乳腺癌是 Li-Fraumeni 综合征女性最常见的恶性肿瘤,由种系TP53致病变异引起。一再提出,来自TP53携带者的乳腺肿瘤比非携带者更可能是 HER2+,但该信息尚未纳入TP53的变异解释模型. 乳腺肿瘤病理学已被用于定量评估其他基因种系变异的致病性,并且有人建议将此类证据纳入当前的美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP)种系变异分类指南。在这里,通过审查已发表的数据并使用按不同年龄组分隔的内部数据集,我们研究了乳腺肿瘤 HER2+ 状态是否可用作TP53种系变异致病性的预测因子,同时考虑到诊断时的年龄。总体而言,我们的结果表明,40 岁之前诊断的 HER2+ 乳腺肿瘤的鉴定可以保守地纳入当前的TP53- 特定 ACMG/AMP PP4 标准,遵循本手稿中详述的积分系统。需要进一步更大规模的研究来重新评估在较晚年龄诊断出的 HER2+ 乳腺肿瘤的价值。
更新日期:2020-06-02
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