Supplementary Material for: ATM Variant as a Cause of Hereditary Cutaneous Melanoma in a Spanish Family: Case Report

<b><i>Introduction:</i></b> Ataxia-Telangiectasia Mutated (ATM) is a cancer predisposition gene; carriers of germline pathogenic variants have an increased risk of developing malignancies, including breast, prostate, pancreatic, and ovarian cancer. Most ATM variants are of uncertain significance. Findings from genome-wide association studies (GWAS) suggest that ATM may be a low-risk melanoma susceptibility locus. <b><i>Case Report:</i></b> We report the case of a Hispanic family whose members who have presented cutaneous melanoma have been found to be carriers for the ATM pathogenic variant c.3747-1G&gt;C (rs730881364), one of whom was diagnosed at 24 years old. <b><i>Discussion:</i></b> We describe for the first time the possible clinical association between ATM (c.3747-1G&gt;C) and familial melanoma. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site, assuming a variant that entails loss of functionality that is probably pathogenic and related to oncogenesis. However, we cannot exclude that cutaneous melanoma in both members and at an early age is the result of chance, environmental interaction, other uncontrolled external factors, or the interaction of other genetic alterations other than the ATM variant described in this study.

**引言：** 共济失调毛细血管扩张症突变（Ataxia-Telangiectasia Mutated, ATM）是一种癌症易感基因；生殖系致病变异携带者罹患包括乳腺癌、前列腺癌、胰腺癌以及卵巢癌在内的多种恶性肿瘤的风险显著升高。绝大多数ATM变异属于意义未明变异。全基因组关联研究（Genome-Wide Association Studies, GWAS）结果提示，ATM可能是一个低风险的黑色素瘤易感位点。**病例报告：** 我们报告一个西班牙裔家族的病例：该家族中出现皮肤黑色素瘤的成员均被检出携带ATM致病变异c.3747-1G>C（rs730881364），其中1名患者在24岁时即被确诊。**讨论：** 我们首次阐述了ATM（c.3747-1G>C）与家族性黑色素瘤之间可能存在的临床关联。计算机剪接位点分析预测，该变异会削弱天然剪接接受位点，并可能创建或强化新型剪接接受位点；该变异会导致功能丧失，大概率具有致病性并与肿瘤发生相关。不过，我们无法排除两名患者的早发性皮肤黑色素瘤是由偶然性、环境交互作用、其他未被控制的外部因素，或是本研究所述ATM变异之外的其他遗传变异相互作用所导致的。