In this study, a BRCA2 pathogenic variant was detected in the patient. The BRCA2 exon 13 variant c.C6952T, p.R2318X was identified as a pathogenic variant according to previous studies [7,8,9]. The frequency of this variant has been reported to be 0.44% in Japanese patients with breast cancer [8], and this variant has also been reported in Japanese patients with ovarian cancer [9]. Here, when reviewing the family tree (Fig. 3) with this genetic information, it was apparent that one maternal cousin (III-8) had a history of ovarian cancer, one paternal cousin (III-1) had prostate cancer, and no family member on either side had breast cancer. As prostate cancer is also related to hereditary breast and ovarian cancer (HBOC), it is difficult to determine the family member from whom the BRCA2 variant was derived. Additional examination in other family members should be considered to clarify hereditary tumor involvement and perform segregation analysis.
One of the most important clinical considerations in this case was that the bilateral ovaries of the patient were not resected. In addition, the fallopian tubes were not pathologically examined in accordance with the SEE-FIM protocol at that time. When total laparoscopic hysterectomy and bilateral salpingectomy were performed to treat her endometrial cancer, there was no information regarding her BRCA2 pathogenic variant. On the contrary, this patient did not meet the BRCA1/2 testing criteria of the National Comprehensive Cancer Network Guidelines (v. 3, 2019), as she had no history of breast or ovarian cancer and only one of her cousins had ovarian cancer. Therefore, it was difficult to evaluate the risk of HBOC in this patient using only the personal and family histories. In contrast, if multigene panel testing had been performed before surgery, this patient could have opted bilateral salpingo-oophorectomy based on the future ovarian cancer risk; moreover, the fallopian tubes should have been appropriately examined.
Thus, multigene panel testing may change disease management in clinical settings based on results that cannot be obtained from either conventional risk assessments or single-gene analysis. Indeed, previous studies have indicated that multigene panel testing can increase the detection rate of any pathogenic variant (including non-BRCA1/2 variants, such as Lynch syndrome genes) in patients suspected with HBOC, and this can alter clinical management strategies for cancers [6, 10]. Kurian et al. also reported that BRCA1/2-only testing is being replaced by multiple-gene sequencing for patients with breast cancer [11]. Furthermore, some previous studies identified BRCA2 pathogenic variants in patients with colorectal cancer based on the age at diagnosis or family history of colorectal cancers [12, 13]. Here, we suggest that multigene panel testing is also useful for improving the clinical management strategies of patients who had been primarily suspected to have Lynch syndrome and not HBOC.
However, several issues should be considered when performing multigene panel testing. For example, there may be some differences in the targeted genes or variant annotations among the commercially available tests. The possibility of identifying variants of unknown significance or variants in genes that are not thought to be clinically actionable should also be considered. Therefore, single gene analysis could be considered for some hereditary tumors, which have characteristic phenotypes, such as, Peutz–Jeghers syndrome. Individuals providing genetic counseling should be familiar with updated information regarding the problems mentioned above.
Regarding the relationship between the BRCA1/2 variant and endometrial cancer, Shu et al. reported that the risk of serous/serous-like endometrial carcinoma increased in BRCA1 variant-positive women [14]. In our case, the patient had a BRCA2 pathogenic variant, and the endometrial cancer histology was endometrioid carcinoma. Therefore, it is unclear whether the BRCA2 variant affected the etiology of endometrial cancer. On the contrary, this patient did not have typical clinical features of endometrial cancer such as obesity or a history of diabetes mellitus. Although nulliparity could be a risk factor, it is obscure how the patient developed endometrial cancer in her thirties.
In conclusion, we present a case in which multigene panel testing revealed a BRCA2 pathogenic variant in a patient who had been suspected to have Lynch syndrome, rather than HBOC. Clinicians should take detailed history of patients and their families, particularly when planning a surgery and should carefully choose an appropriate genetic testing tool that may confirm or alter the clinical management strategy.