Low-level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer

Speight, B.; Colvin, E.; Epurescu, E.D.; Drummond, J.; Verhoef, S.; Pereira, M.; Evans, D.G.; Tischkowitz, M.

doi:doi:10.1186/s13053-022-00237-x

Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in similar to 52% of reads in DNA extracted from tumour, similar to 10% of reads in DNA extracted from peripheral blood leukocytes and similar to 10% of reads in DNA extracted from buccal mucosa. The second BRCA c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in similar to 59% of reads in DNA extracted from tumour, similar to...Show moreGermline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in similar to 52% of reads in DNA extracted from tumour, similar to 10% of reads in DNA extracted from peripheral blood leukocytes and similar to 10% of reads in DNA extracted from buccal mucosa. The second BRCA c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in similar to 59% of reads in DNA extracted from tumour, similar to 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in similar to 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.Show less

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Low-level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer