References
Overview
ACCURATE CLASSIFICATION OF BRCA VARIANTS
Clinical management decisions depend on accurate classification of BRCA variants
| Example Mutation | Previously reported variant with a recognised deleterious impact. [1] E.g. early termination of the protein [2] |
| Impact on patient management | Disease-associated mutation detected [3] Result can be used for clinical management of the patient [4] |
| Predictive testing*[5] | Yes |
| *Predictive testing: clinical test offered to at-risk family members [6] | |
| 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 codon [7] |
| Impact on patient management | Treat as Class 5 patients, despite small risk of over-treatment [8] Result can be used for clinical management[9] May warrant additional follow up studies to assess significance and potentially reclassify, e.g. segregation studies, tumour histopathology, in vitro assays [10] |
| Predictive testing*[11] | Yes |
| *Predictive testing: clinical test offered to at-risk family members[12] | |
| Example Mutation | A previously unreported missense variant in an evolutionarily conserved amino acid (the position may or may not result in pathogenic characteristics)[13] |
| Impact on patient management | VUS detected: Clinical significance unknown[14] No evidence to change the clinical management of the patient[15] - Management plan based on family history and other risk factors[16] May warrant further follow up studies to clarify significance[17] |
| Predictive testing*[18] | No |
| *Predictive testing: clinical test offered to at-risk family members[19] | |
| 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 predicted[20] |
| Impact on patient management | Treat as “no mutation detected”[21] No evidence to change clinical management[22] Additional tests possible, if the analytical techniques used do not cover certain mutation types Further follow up studies may help reclassification to class1[23] |
| Predictive testing*[24] | No |
| *Predictive testing: clinical test offered to at-risk family members[25] | |
| Example Mutation | Variants that are previously reported and are recognised as neutral variants[26] |
| Impact on patient management | Treat as “no mutation detected”[27] No evidence to change clinical management[28] Additional tests possible, if the analytical techniques used do not cover certain mutation types |
| Predictive testing*[29] | No |
| *Predictive testing: clinical test offered to at-risk family members[30] | |
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[20]
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[24]
[25]
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[30]
Overview
References
Testing the family
Importance of BRCA testing family members upon identification of a germline BRCA mutation.
Veeva ID: Z4-10833 Date of preparation: May 2018; Date of expiry: May 2020
Dr Emma Howard video
Dr Emma Howard discusses best practice interpretation of BRCA mutations.
Veeva ID: Z4-10833 Date of preparation: May 2018; Date of expiry: May 2020