Reclassification of BRCA1/2 variants previously classified as VUS (ACMG-AMP guidelines) with gene-specific guidelines from ClinGen ENIGMA and CanVIG-UK

Rodrigues, Pedro; Theisen, Patrícia; Gonçalves, João

http://hdl.handle.net/10400.18/9151

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Authors

Rodrigues, Pedro

Theisen, Patrícia

Gonçalves, João

Abstract(s)

In recent years, the number of BRCA1/2 germline variants associated with hereditary breast/ovarian cancer syndrome (HBOC), classified as variants of uncertain significance (VUS) according to ACMG-AMP guidelines (ACMGg) has been increasing. Reclassification of VUS as (likely) benign or (likely) pathogenic is crucial for maximizing diagnostic yield and appropriately managing HBOC patients. Recently, specific guidelines to improve classification of BRCA1/2 variants were independently developed by ClinGen ENIGMA1 (CG-Eg) and CanVIG-UK2 (CV-UKg). Main goals: i) independently reclassify BRCA1/2 variants previously classified as VUS (ACMGg) with the new guidelines (CG-Eg and CV-UKg); ii) compare the results between the different guidelines iii) evaluate the potential clinical impact of this reclassification. BRCA1/2 germline variants identified in patients with suspected HBOC and previously classified as VUS (8 missense, 5 intronic) were independently reclassified according to CG-Eg and CV-UKg. Variant assessment included: query of clinical/population databases and use of VEP, Alamut, VarSome and Franklin-Genoox. VUS reclassification (using CG-Eg versus CV-UKg) was in agreement for 10 variants (2 VUS, 6 likely benign (LB) and 2 benign (B)). The remaining 3 VUS were reclassified as LB with CG-Eg and kept as VUS with CV-UK. Application of specific guidelines reduced the number of VUS from 10 to 2 (CG-Eg) or to 5 (CV-UKg). The main difference between CG-Eg and CV-UKg is related with the downgrading strength of PM2 and the upgrading strength of BP1 criteria (in CG-Eg) for missense variants present outside clinically important functional domains and without splicing impact. The difference in BP1 strength has a major impact, making CG-Eg more stringent and reducing the number of VUS. The use of different guidelines, even if gene-specific, can lead to dissimilar classifications, a general consensus leading to a unique international guideline will be useful.