Why are cancer panels considered for Hereditary Breast and Ovarian Cancer instea

[Anonymous]

Why are cancer panels considered for Hereditary Breast and Ovarian Cancer instead of just BRCA1 and BRCA2?

[Sana Fathima K S]

While BRCA1 and BRCA2 remain the genes most strongly and most commonly associated with Hereditary Breast and Ovarian Cancer syndrome, they do not account for all cases of inherited breast and ovarian cancer risk within a family, which is why a broader multigene cancer panel is now frequently recommended instead of testing these two genes in isolation.

Clinical experience and large-scale studies have shown that a meaningful proportion of individuals who meet the clinical criteria for hereditary breast and ovarian cancer testing, yet test negative for BRCA1 and BRCA2, go on to be found positive for a mutation in another moderate- or high-risk gene when a panel is used, including PALB2, CHEK2, ATM, RAD51C, RAD51D, TP53, PTEN, STK11, and CDH1, among others. Each of these genes carries its own distinct pattern and magnitude of cancer risk. For example, PALB2 mutations confer a breast cancer risk that approaches the risk seen with BRCA2 mutations, RAD51C and RAD51D mutations are more specifically linked to elevated ovarian cancer risk with a comparatively lower breast cancer risk, TP53 mutations are associated with Li-Fraumeni syndrome and a very broad multi-organ cancer risk profile beginning in childhood, and CDH1 mutations are linked to hereditary diffuse gastric cancer alongside lobular breast cancer risk. Because the clinical presentation of families carrying mutations in these different genes can overlap substantially with families carrying BRCA1 or BRCA2 mutations, relying on BRCA1 and BRCA2 testing alone risks missing a hereditary cancer diagnosis, which in turn means the individual would not be offered the gene-specific surveillance, risk-reducing surgery timing, or targeted treatment options that would otherwise be available to them.

A multigene panel also offers practical and financial efficiency, since testing several relevant genes simultaneously using a single blood or saliva sample is generally more cost-effective and faster than testing genes one at a time in succession. However, panel testing also carries the added complexity of a higher chance of identifying a variant of uncertain significance, meaning a genetic change whose relationship to cancer risk is not yet clearly established, which requires careful pre-test and post-test genetic counselling so the individual understands that such a result does not currently change medical management. In the Indian context, where population-specific mutation spectrum data is still being established, panel testing is particularly useful because it captures a wider range of possible pathogenic mutations that may not yet be as well characterised in local Ashkenazi-style founder mutation databases, thereby improving diagnostic yield for Indian patients and families being evaluated for Hereditary Breast and Ovarian Cancer syndrome.

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