How are BRCA1 and BRCA2 mutations defined?

By “mutation positive” the CanRisk Tool means a mutation that is thought to be associated with an increased risk of cancer.

There are several types of mutation in BRCA1 and BRCA2. Some are thought to be associated with cancer risk (deleterious mutations). Others are thought to be unrelated to cancer (polymorphisms). For many mutations, it is uncertain whether there is an association with cancer or (variants of uncertain significance, or VUS). You are advised not to include VUSs as mutations.

As a general rule, deleterious mutations include:

• Frameshift mutations

• Nonsense mutations

• Splice site mutations involving the consensus splice sequence (+1/+2/-1/-2 positions)

• Large deletions or duplications (involving whole exons) or other large rearrangements

• A limited number of missense mutations (amino-acid substitutions), principally involving cysteines in the ring finger of BRCA1

• Polymorphisms include all variants which occur at significant frequency in the population (1% or more).

Variants of uncertain significance include:

• In-frame deletions or insertions

• Splice-site mutations not involving the consensus splice sequence

• Most missense mutations