Prior to the genetics referral, patient 1 was informed of the BRCA1 result by her Oncology team. After the referral, a clinic appointment for further genetic counselling was arranged. This was virtual due to the COVID-19 pandemic. Patient-initiated topics covered in the first genetic counselling session included the likelihood of this result as the cause of ovarian cancer and the implications for family members. This led on to establishing a family history record and a discussion of mosaicism as a factor that influences risk to relatives. Prior to information provision, the patient’s understanding of the result and her concept of mosaicism were established. Mosaicism was explained avoiding the use of specialised/medical terminology. Use of visual aids to help understanding was prevented by a transition to telephone-based appointments early in the pandemic. The patient seemed reassured that the chance of wider family members having the variant was unlikely, given the mosaic finding. Revertant mosaicism of a parentally inherited variant has never been reported for BRCA1, but could not be excluded since both parents were deceased. Predictive testing in a sibling subsequently gave a negative result. The patient was accepting of the up to 50% chance of having passed it on to her children, due to the possibility the gonadal cell line was derived from embryonic cells containing the variant. Predictive testing in her children was safely deferred based on their young age.

Genetic counsellor-initiated topics covered in the first session with patient 1 and in the results session of patient 2 included BRCA1-associated hereditary predisposition to breast and ovarian cancer, risk management options, psychosocial impact of cancer treatment/genetic testing and cancer risk perception. To exclude circulating tumour cells or clonal haematopoiesis as alternative reasons for low-level mosaicism in DNA from peripheral blood leukocytes, further testing of another non-neoplastic tissue was suggested.

Quantifying breast cancer risk associated with a mosaic BRCA1 variant was complicated by the impossibility of predicting the proportion of breast tissue with the (likely/) pathogenic variant. Theoretically, mosaicism for BRCA1 may not give rise to risk equivalence of constitutional carriers and there is likely ascertainment bias in the few reported mosaic cases in women with young-onset cancer. Given there is no basis on which to reliably predict a milder phenotype of reduced cancer risks or later-onset diagnosis, evidence-based BRCA1 risk ranges were provided to both patients [12], alongside standard clinical care for BRCA1 carriers.

At present, the best individualised breast cancer risk assessments in constitutional BRCA1/BRCA2 carriers are estimated using a validated programme such as CanRisk [14]. This can take into account carrier status, age, family history, lifestyle, hormonal factors and polygenic risk scores. It was not possible to quantify breast cancer risk for our patient in this way due to insufficient data to inform the model on breast cancer risk after ovarian cancer. Even in a patient who has not had a previous cancer, the CanRisk model, which is otherwise transforming patient care, will not enable individualised risk assessment in the context of a mosaic result. Risk management of further cancers was not described in the three published reports of BRCA1 mosaicism [4, 8, 9] or the report of BRCA2 mosaicism in ovarian cancer [10]. In the report of a mosaic BRCA2 carrier with a history of breast cancer, risk-reducing mastectomy and bilateral salpingo-oophorectomy was offered and taken up following discussion of the genetic result [2].

Based on the BRCA1-associated breast cancer risk, annual breast MRI surveillance was offered and organised for both patients. When to discuss risk-reducing mastectomy in BRCA1/BRCA2 carriers after a diagnosis of advanced stage ovarian cancer can be a challenging area in providing patient-centred genetic counselling [19]. Within the first couple of years after this diagnosis, the focus is usually on active treatment with an intention to prevent or delay relapse. Risk-reducing breast surgery options were not raised in these sessions, with an awareness that the risk/benefit ratio of cancer risk management strategies will change over time.

A plan was made for further testing on a buccal epithelium sample on both patients, and urine sample for patient 2, before arranging follow up appointments. Given the strong concordance in the variant allele frequency of the pathogenic variant between buccal brush sample and blood this was felt to be sufficient evidence to guide clinical management. If the results had been discordant, then fibroblasts from a skin biopsy would have been another source of DNA. At follow up, the result confirming low-level mosaicism in another non-cancer tissue and a review of previous information and topics were covered. Although offspring risks would likely be below 50% as more than one non tumour tissue showed similar rates of mosaicism, tentative likelihoods of 1 in 10 (10% allele frequency) and 1 in 7 for 14% could be used.