The BRCA1 c.4096+1G>A Is a Founder Variant Which Originated in Ancient Times

Area of Science:

• Genetics
• Oncology
• Population Genetics

Background:

• Germline pathogenic variants in BRCA1 and BRCA2 genes account for 30-50% of hereditary breast and ovarian cancer (HBOC).
• Women with pathogenic BRCA1 variants face significantly increased risks for breast cancer (45-79%) and ovarian cancer (39-48%).
• The BRCA1 c.4096+1G>A variant is prevalent in Tuscany, Italy, and has been observed globally, with evolving classification from uncertain to pathogenic significance.

Purpose of the Study:

• To investigate the origins and evolutionary history of the BRCA1 c.4096+1G>A founder variant.
• To determine the time to the most recent common ancestor (MRCA) for carriers of this specific BRCA1 variant.

Main Methods:

• Genotyping of 48 subjects (38 carriers) from 27 families using the Illumina OncoArray Infinium platform.
• Haplotype analysis of a 20 Mb region surrounding the BRCA1 gene, including 4130 single nucleotide polymorphisms (SNPs).
• Phylogenetic methods were employed to estimate the MRCA of the BRCA1 c.4096+1G>A variant.

Main Results:

• The study identified 38 carriers of the BRCA1 c.4096+1G>A variant across 27 families.
• Haplotype analysis focused on a 20 Mb region around the BRCA1 gene.
• Phylogenetic analysis estimated the MRCA of the BRCA1 c.4096+1G>A founder variant to be approximately 155 generations ago, equating to about 3000 years.

Conclusions:

• The BRCA1 c.4096+1G>A variant, a significant contributor to HBOC in certain populations, has a deep evolutionary root.
• The findings suggest a long-standing presence of this founder variant, providing insights into its historical prevalence and potential impact on cancer risk over millennia.