To the Editor,

Accurate interpretation of BRCA1 and BRCA2 variants is important for risk assessment and treatment of BC. Currently, available databases of BRCA1/2 variants are mainly derived from the Caucasian population and may not be suitable for use in the Chinese population due to considerable ethnic differences. In a previous study, Sun et al. examined BRCA1/2 variants in 8085 Chinese BC patients, however without the inclusion of healthy controls in the study [1]. During a period from 10-01-2015 to 12-15-2018, we collected 21,216 unselected Chinese BC patients and 6434 healthy controls in 19 medical centers in 11 Chinese provinces (Additional file 1: Fig. S1). Subjects and methods are shown in detail in the Additional file 2. Panel-based sequencing identified a total of 1958 BRAC1/2 variants. Based on the ClinVar database (clinvar_20171002.vcf.gz) and ACMG guidelines, 532 (27.2%) variants are pathogenic, 858 (43.8%) are VUS, and the remaining 568 variants (29.0%) are benign (Additional file 3: Table S1).

Percentages of the subjects carrying pathogenic variants were 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls (Additional file 3: Table S1). A complete list is presented in Additional file 4: Table S2. The following 13 pathogenic variants had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients): p.Cys328fs, p.Asn704fs, p.Ser1862fs, and p.Ile1845fs in BRCA1; p.Ala938fs, p.Gln1037*, p.Ser1722fs, p.Tyr1894*, p.Leu1908fs, p.Glu2198fs, p.Ser2378*, p.Pro2802fs, and p.Thr3033fs in BRCA2. Among these 13 variants, 8 variants are reported for the first time as high-frequency variants, none has been reported as high-frequency variants in Caucasians, one (p.Cys328fs) has been reported at high frequency in Korean patients [2] (Fig. 1), and the remaining 4 variants (p.Ser1862fs, p.Ile1845fs, p.Gln1037*, p.Tyr1894*) have been reported at high-frequency in other Chinese studies [1, 3].

Fig. 1
figure 1

High-frequency BRCA1/2 pathogenic variants distribution in Europe and USA, Asia*, and our study. Europe and USA: Include Ashkenazi Jew, Icelander, Norwegian, Finns, Swede, French, Dutch, Italian, French-Canadian, Hispanics (South California), Hispanics (Columbia), Afro-American, South African; Asia*: Include Iraqi/Iranian Jew, Singaporean, Filipino, Pakistani, Japanese, and Korean. a High-frequency BRCA1 pathogenic variants distribution in Europe and USA, Asia*and China. Domains are Zinc/Ring finger (green); Serine cluster domain (blue); BRCT domain (red); BRCT (C terminus) (yellow). Variants in different region are indicated by color: blue: Europe and USA; green: Asia*; red: our study. One dot represents one variant; gray line length represents the number of groups with the variant. b High-frequency BRCA2 pathogenic variants distribution in Europe and USA, Asia*and China. Domains are BRCA repeats (green); BRCA helica (red); OB binding domain (blue); tower (yellow) and OB3 binding domain (purple). Variants in different region are indicated by color: blue: Europe and USA; green: Asia*; red: our study. One dot represents one variant; gray line length represents the number of groups with the variant

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In comparison with patients without BRCA1/2 pathogenic variants (n = 16,472), both the patients carrying BRCA1 (n = 404) and BRCA2 pathogenic variants (n = 544) were younger, and more likely of having higher histological grade, having invasive carcinoma vs. ductal carcinoma, and having a family history of BC. BRCA1 pathogenic variants were associated with TNBC and bilateral lesions, whereas BRCA2 pathogenic variants were associated with Luminal B type (Additional file 5: Fig. S2 and Additional file 6: Table S3).

Percentages of the subjects carrying VUS were 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls (Additional file 3: Table S1). 7 out of the 858 VUS had > 0.1% allele frequency in the entire cohort and no statistical difference between the patients and controls in our cohort, and thus were re-grouped into benign variants (Additional file 7: Table S4). The re-classification resulted in lower VUS ratio in patients (from 9.8 to 7.9%) and healthy controls (from 6.9 to 5.3%).

We next re-analyzed the 100 variants in 13 exons (2–5 and 15–23) of the BRCA1 gene using a functional assay (saturation genome editing; SGE), as reported by Findlay et al. [4]. Under the ClinVar database and ACMG guidelines, 38 were pathogenic, 59 were VUS, and the remaining 3 were benign. 2 of the 38 pathogenic variants had distinct status in the Findlay study: one was VUS and another was benign. 55 of the 59 VUS had distinct status in the Findlay study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign (Additional file 8: Table S5). Notably, the 24 pathogenic variants under the functional assay were detected in BC patients only in our cohort. All 3 benign variants were also considered benign in the Findlay study .

In comparison with the 101 BC patients having VUS in the 13 BRCA1 exons under the ClinVar database and ACMG guidelines, subjects re-grouped to pathogenic variants by SGE (24 variants, 38 pts) had higher rate of TNBC (50% vs 34.3%, p = 0.465), higher rate of early onset (36.8% vs. 26.7%, p = 0.516), and higher rate of having family history of BC (15.8% vs 8.9%, p = 0.465). In contrast, subjects re-grouped from VUS to benign (31 variants, 58 pts) had a lower rate of TNBC (24.3% vs 34.3%, p = 0.569), lower rate of early onset (20.7% vs 26.7%, p = 0.630), and lower rate of family history of BC (5.2% vs 8.9%, p = 0.626) (Table 1).

Table 1 Distribution proportion of 3 groups of BRCA1 variants carriers clinical characteristics
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In summary, the current study demonstrated distinct BRCA1/2 variant profiles in Chinese patients with BC, as well as healthy donors, and suggested testing based on hotspots in Caucasian patients/population is not appropriate. Hence, there is a need to develop a classification system that categorizes the known variants into pathogenic, VUS, and benign in the Chinese population. The biological impact of variants in the literature, allele frequency in the Chinese patients, and the general Chinese population should be incorporated into this classification system.