We recently published a study that brings attention to “reduced penetrance” BRCA1 and BRCA2 (BRCA) mutations, which lead to LOWER breast cancer risks than “typical” BRCA mutations.1 Specifically, these mutations lead to a lifetime breast cancer risk of 20-30%, similar to moderate penetrance breast cancer genes such as CHEK2 or ATM. This level of risk does not typically warrant the option for risk-reducing mastectomy, although high-risk screening with breast MRI and mammograms would continue to be recommended. The specific variants included in this paper are outlined in Table 1 below (also posted to our social media accounts @inheritedcancer). This work, done by our team at Vanderbilt, Moffitt, and Mayo, in collaboration with our commercial laboratory colleagues at Ambry and Myriad, is ongoing and just the beginning. More variants like this will be identified, and it is important to define and clarify this new class of variants in order to refine risks and contribute to improving patient care.
Table 1: Specific BRCA1 and BRCA2 Variants
| BRCA1 | BRCA2 |
| c.5096G>A | c.658_659delGT |
| c.671-1delins6 | c.9672dupA |
| c.671-2A>T | c.9699_9702delTATG |
| c.671-2A>G | c.7878G>C |
| c.671-2A>C | c.7878G>T |
| c.671-1G>T | c.9302T>G |
| c.671-1G>C | c.8488-1G>A |
| c.671-1G>A | c.8488-1G>T |
Another subsequently published article led by the team at Mayo tried to classify over 6000 BRCA2 missense variants (meaning a change in the amino acid that does not typically shorten the protein and can often lead to a Variant of Uncertain Significance (VUS) classification)
using various databases and laboratory studies.2 Because VUS results are not useful in directing care, better strategies to characterize these results are needed. The team was able to classify 91% of 6960 variants. This is important to improve risk assessment and management in those with a variant in BRCA2.
Check out an overview of this missense variant work by Dr. Couch at: https://youtu.be/HpTDRRJ3c4U
1Pal, et al. NPJ Precis Oncol. 2024;8(1):247. PMID: 39488595. Article available at: https://tinyurl.com/39488595. Social media post available at: https://tinyurl.com/post11112024. An overview by Dr. Tuya Pal is available on our ICARE YouTube channel at: https://youtu.be/CZI46jH3DJY; 2Huang, et al. Nature. 2025;638(8050):528-537. PMID: 39779857. Article available at: https://tinyurl.com/39779857. Social media post available at: https://tinyurl.com/post2132025.