Background When germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity. Methods We present here a real world example of the c.256G > A CDKN2A variant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation. Results This c.256G > A CDKN2A variant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother’s 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that the CDKN2A variant was ‘likely pathogenic’ and the disease was defined as ‘likely hereditary melanoma’. Conclusions The pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with ‘practically’ unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.

中文翻译：

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告知患者他们的突变测试：以黑色素瘤中的 CDKN2A c.256G>A 为例

背景 当怀疑生殖系突变是癌症的原因时，可以对患者 DNA 进行测序以检测相关基因中的变异。如果在可靠的家庭研究中没有报告特定突变，遗传咨询师将面临适当告知患者的两难境地。许多测序设施根据可用的序列数据库或从生物信息学和机械数据集整理的预测工具提供对发现的解释。如果谱系数据不提供信息但计算机预测表明致病性，则咨询困境会加剧。方法 我们在此展示 c.256G > A CDKN2A 变体的真实世界示例，该变体在一名黑色素瘤患者中检测到，其中两个兄弟姐妹被原位诊断为黑色素瘤。我们调查了受影响兄弟姐妹的详细家族史，以调查这种突变背景下癌症风险的概率。结果 在其中一个兄弟和无黑色素瘤的母亲中检测到这种 c.256G > A CDKN2A 变体，而家庭中的另一个兄弟检测为阴性。先前已在来自黑色素瘤家族的一名患者中描述了该变体。在接受调查的家庭中，母亲的 16 名一级和二级亲属存活超过黑色素瘤的中位发病年龄，没有人出现黑色素瘤。我们使用多种生物信息学工具测试了该变体，所有这些工具都预测了该变体的有害性。给黑色素瘤患者的遗传咨询报告指出，CDKN2A 变异是“可能致病的”，该疾病被定义为“可能的遗传性黑色素瘤”。结论 谱系数据最多显示低外显率变异，如果考虑到这一变异，可能会改变所提供的诊断。在处理“几乎”未知的变异时，建议顾问结合详细的家族史，而不是根据测序设施提供的功能进行预测。