Case report: a rare BRCA1 de novo variant in a female with breast cancer.

Background
Breast cancer is the most common malignancy among women worldwide, with an incidence of 47 per 100.000 women [1]. 5-14.1% of breast cancer cases are attributable to pathogenic genetic variants in common breast cancer genes, with pathogenic variants in the BRCA1 gene being a well-known cause [2, 3]. BRCA1 variants are inherited in an autosomal dominant manner. Consequently, these variants are frequently associated with a notable family history of the disease, and family history remains a central criterion for genetic testing.
According to established guidelines (such as the HBOC (Hereditary Breast and Ovarian Cancer) or NCCN (National Comprehensive Cancer Network) criteria [4, 5]), individuals undergo genetic testing if they meet specific clinical or familial risk factors, including early-onset breast cancer, triple-negative phenotype, bilateral disease, or a family history of breast or ovarian cancer. A genetically confirmed pathogenic variant in one of the breast cancer susceptibility genes (e.g. BRCA1) qualifies patients to participate in intensive early detection program and consideration of risk-reducing surgery. Although most BRCA1 variants are inherited, de novo variants can occur.
In the general population, the rate of de novo variants is estimated in a total of 98–206 de novo pathogenic variants per transmission [6]. The highest incidence of pathogenic de novo variants is observed in neurodevelopmental and developmental disorders, where up to 42% of individuals with severe, undiagnosed developmental disorders carry pathogenic de novo variants in coding sequences [7]. The incidence of pathogenic de novo variants in cancer is generally low, and specifically, the incidence of pathogenic de novo variants in BRCA1 and BRCA2 genes is 0.3% among BRCA1/2 pathogenic variant carriers [8].
To date, only twelve cases of de novo BRCA1 variants have been reported in the literature, often with unremarkable family histories [8–17]. In this case report, we describe another instance of a young woman with breast cancer who had no remarkable family history and was found to carry a pathogenic de novo BRCA1 variant.

Case presentation

Patients presentation
We present a case study of a 37-year-old female patient who was diagnosed with an invasive carcinoma of the right breast in 2022. The family history was unremarkable with regard to genetic tumour predisposition syndromes, in particular breast and ovarian cancer (see Supplement Fig. S1). An initial ultrasound examination identified a tumour measuring 1.1 × 0.6 × 5.0 cm, a finding that was subsequently confirmed by magnetic resonance imaging. No additional lesions suggestive of metastatic disease were detected on imaging. The patient underwent neoadjuvant systemic therapy consisting of 12 cycles of paclitaxel combined with dual receptor blockade, followed by four cycles of epirubicin and cyclophosphamide chemotherapy. Surgical management entailed breast-conserving surgery (lumpectomy) with a sentinel lymph node biopsy. Histopathological evaluation revealed a tumour with 100% positivity for oestrogen receptor (ER) and progesterone receptor (PR). Human epidermal growth factor receptor 2 (HER2/neu) status was scored as 3 + by immunohistochemistry. The Ki-67 proliferation index was quantified at 35%. Tumour staging at diagnosis was clinical T1c N0 M0, with a histological grade of G3. Following surgery, the patient underwent adjuvant therapy with trastuzumab emtansine for approximately one year due to residual tumour disease, alongside ovarian suppression using gonadotropin-releasing hormone agonists and aromatase inhibitors. Additionally, adjuvant radiotherapy was administered to the right breast. Since November 2022, the patient has undergone adjuvant endocrine therapy, comprising letrozole and Goserelin in conjunction with neratinib for one year, a HER2-directed tyrosine kinase inhibitor.

Genetic testing
Genetic counselling and germline genetic testing using Next Generation Sequencing (NGS) of the patient were performed in 06/2024 in another clinic, identifying a pathogenic heterozygous variant NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9) in the BRCA1-Gene. We performed a diagnostic NGS panel analysis covering all known cancer-associated genes (including the most relevant HBOC Core-genes), using genomic DNA extracted from peripheral blood leukocytes to confirm the previously known variant. Panel analysis was performed using Next-Generation-Sequencing via TWIST targeted enrichment following by short read sequencing on a NovaSeq6000 (Illumina) without detecting a mosaic. Variant nomenclature followed HGVS guidelines, with genomic positions referenced to hg38 [18]. Variant classification adhered to ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 v1.2 [19].
The deletion of the two nucleotides leads to a frameshift and consequently to a premature stop codon (ACMG criteria applied: PVS1, PM5_STR_PTC), most likely resulting in a missing or disrupted protein product. This variant does not occur in the general population (gnomAD: 0%, v.4.1.0, ACMG criterion applied: PM2_SUP) [20]. It is listed twice in the HGMD database (ID: CD044265) [21]. The variant was assessed as pathogenic 6 times in ClinVar (ID: 54205) [22].
The polygenic risk score (PRS) for breast cancer was 1.6071 (z-score), placing the patient at the 95th percentile of the reference distribution; however, this value is still considered within the normal range. The genetic ancestry was calculated as European. The breast cancer PRS was calculated based on 313 breast cancer–associated variants (BCAC313) as defined by Mavaddat et al. [23]. We calculated the PRS for the following reasons: For carriers of pathogenic variants in core breast cancer genes, the PRS can help further refine individual risk estimates [24–26]. The PRS can also provide information about the risk of developing cancer in the opposite breast [27]. At our centre, the PRS assessment is fully integrated into routine diagnostic care, allowing us to tailor risk management and counselling to each patient’s unique genetic profile.
Subsequently, the patient’s biological parents attended our genetics clinic for cascade testing to determine their carrier status for the familial BRCA1 pathogenic variant in 2025. We performed the abovementioned NGS analysis to segregate for the BRCA1-variant. However, genetic testing of the patient’s biological parents did not reveal the familial BRCA1 variant, indicating that the patient had a de novo variant. Low level germ cell mosaicism cannot be excluded. To ensure the genetic parentage, we performed a microsatellite analysis. Six out of nine markers were informative for the confirmation of parenthood.

Discussion
Since 1999, 12 de novo BRCA1 pathogenic variants have been reported (Table 1). A striking aspect of de novo variants is the absence of a significant family history. While some patients reported limited cancer history in relatives (e.g., paternal or maternal cousins with breast cancer [8, 11, 12, 14, 16, 17] it is important to note that the presence of breast cancer in more distant relatives may reflect the overall high prevalence of breast cancer in the general population (13.2% in Germany), rather than indicating a hereditary cancer syndrome [28].
Although the variant was not detected in parental blood, the possibility of low-level parental mosaicism, particularly gonadal mosaicism, cannot be entirely excluded by testing blood samples. As the patient has no siblings, there are no additional individuals available for testing who could provide indirect evidence for or against parental mosaicism.
The presented patient underwent genetic testing despite not meeting the German HBOC criteria that would typically justify genetic diagnostic [29]. She was not diagnosed before the age of 36, did not present with triple-negative breast cancer, and had no notable family history of the disease. The reason for external testing two years after the initial diagnosis remains unclear.
In Germany, in cases of de novo variants in breast cancer genes, patients are generally only offered genetic testing once they already developed breast or ovarian cancer, since their family history is often unremarkable and preventive testing in relatives is not typically justified. Without testing, a de novo pathogenic variant would remain undetected, potentially delaying appropriate surveillance and risk reducing surgery (mastectomy and/or salpingo-oophorectomy) for both the patient and her children. Furthermore, the patient’s children are now eligible for genetic testing—an entitlement they would not have had if the pathogenic BRCA1 variant had not been identified in the patient.
Broader access to comprehensive sequencing and inclusion in the German Consortium-HBOC surveillance program are essential to ensure that both patients and their families receive appropriate risk assessment, surveillance, and preventive care. With more comprehensive sequencing now available, the true frequency of de novo BRCA1 pathogenic variants may be higher than the currently assumed 0.4% [8, 18]. To not oversee patients without positive family history, broadening of inclusion criteria for genetic testing can be discussed.
We present another rare case of a de novo BRCA1 variant in a young breast cancer patient. Pathogenic de novo BRCA1 variants, though rare, are clinically significant and may be underdiagnosed due to historical testing limitations and reliance on family history, as well as the lack of parental testing, especially in older patients where parents are often no longer available for analysis. Our case reinforces the need for genetic testing in all breast cancer patients with early onset or aggressive subtypes, regardless of family history.

Supplementary Information
Below is the link to the electronic supplementary material.