Accurate classification of BRCA variants

Clinical management decisions depend on accurate classification of BRCA variants

The proposed IARC 5 – tier classification system for sequence variants identified by genetic testing.

Class 5: Definitely pathogenic

Example Mutation

Previously reported variant with a recognised deleterious impact.REF

E.g. early termination of the proteinREF

Impact on patient management

Disease-associated mutation detectedREF

Result can be used for clinical management of the patientREF

Predictive testing*REF Yes
*Predictive testing: clinical test offered to at-risk family membersREF

Class 4: Likely pathogenic

Example Mutation Variants that are previously unreported but are expected to be deleterious, for example variants that are predicted to shift the mRNA reading frame, or variants that will result in the introduction of a stop codonREF
Impact on patient management

Treat as Class 5 patients, despite small risk of over-treatmentREF

Result can be used for clinical managementREF May warrant additional follow up studies to assess significance and potentially reclassify, e.g. segregation studies, tumour histopathology, in vitro assaysREF

Predictive testing*REF Yes
*Predictive testing: clinical test offered to at-risk family membersREF

Class 3: Uncertain

Example Mutation A previously unreported missense variant in an evolutionarily conserved amino acid (the position may or may not result in pathogenic characteristics)REF
Impact on patient management

VUS detected: Clinical significance unknownREF

No evidence to change the clinical management of the patientREF - Management plan based on family history and other risk factorsREF

May warrant further follow up studies to clarify significanceREF

Predictive testing*REF No
*Predictive testing: clinical test offered to at-risk family membersREF

Class 2: Likely not pathogenic or of little significance

Example Mutation Previously unreported variants that do not produce amino acid substitutions, or a variant that is in an intron and is unlikely to affect splicing. Ultimately no effect on protein function is predictedREF
Impact on patient management

Treat as “no mutation detected”REF

No evidence to change clinical managementREF

Additional tests possible, if the analytical techniques used do not cover certain mutation types

Further follow up studies may help reclassification to class1REF

Predictive testing*REF No
*Predictive testing: clinical test offered to at-risk family membersREF

Class1: Not pathogenic or of no significance

Example Mutation Variants that are previously reported and are recognised as neutral variantsREF
Impact on patient management

Treat as “no mutation detected”REF

No evidence to change clinical managementREF

Additional tests possible, if the analytical techniques used do not cover certain mutation types

Predictive testing*REF No
*Predictive testing: clinical test offered to at-risk family membersREF

You might also like

Testing the family

Importance of BRCA testing family members upon identification of a germline BRCA mutation.

View more

Dr Emma Howard Video

Dr Emma Howard discusses best practice interpretation of BRCA mutations.

View more