Description

The tracks listed here contain data from the ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1/BRCA1 Version 1.1.0. The ENIGMA VCEP has adapted the ACMG-AMP codes for the BRCA1 and BRCA2 genes. These include the codes PVS1 (modified PVS1 decision tree), PS3/BS3 (functional data), PP4/BP5 (multifactorial data), PM5_PTC (PTC data, at exon level), the (potentially) clinically important functional domains defined by ENIGMA, and prediction programs (SpliceAI and BayesDel for PP3/BP4).

The data required for the application of these ENIGMA codes are displayed in 5 data tracks:

• BRCA1/BRCA2 protein domains 1.1.0 - Shows the (potentially) clinically important functional domains for the genes BRCA1 and BRCA2 as defined by ENIGMA. Data taken from Figure 1 of the guidelines document CSpec_BRCA12ACMG-Rules-Specifications_V1.0_23-04-27.
• BRCA1/BRCA2 exon weights 1.1.0 - This track shows exon-specific weights for PM5_PTC ACMG code with evidence strong used for application of this code for novel protein termination codon (PTC) variants in an exon where a different proven pathogenic PTC variant has been seen before. Data taken from guidelines document CSpec_BRCA12ACMG_Rules-SupplementaryTables_V1.0_23-04-27.
• BRCA1/BRCA2 functional assays 1.1.0 - Summary of BRCA1 and BRCA2 functional assay results reviewed for application of PS3 and BS3 ACMG codes Data taken from guidelines document CSpec_BRCA12ACMG-Rules-Specifications_V1.0_Table-9_23-04-27.
• BRCA1/BRCA2 splicing 1.1.0 - Summary of ACMG codes applicable for variants considered against the BRCA1 and BRCA2 PVS1 decision trees. Includes PVS1 and PM5 codes recommended for initiation, nonsense/frameshift, deletion, duplication, and splice site (donor/acceptor ±1,2) variants– organized by exon. Data taken from guidelines document CSpec_BRCA12ACMG-Rules-Specifications_V1.0_Table-4_23-04-27.
• BRCA1/BRCA2 likelihood for PP4 and BP5 - Summary of BRCA1 and BRCA2 multifactorial likelihood analysis scores (displayed as Combined LR score) for ACMG codes PP4 and BP5. Combined LR scores were recalculated from 4 sources, Parsons et al. 2019, Caputo et al 2021, Li et al 2020, and Easton et al 2007. All individual scores can be seen by clicking on the items. See the Methods section below for more information.

Display Conventions

• BRCA1/BRCA2 protein domains 1.1.0 - Items in fuchsia show clinically relevant protein domains. Mouseover on items shows the name of the domain and the location.
• BRCA1/BRCA2 exon weights 1.1.0 - Mouseover on exons (black items) show the transcript, exon number and the PM5_PTC code strength.
• BRCA1/BRCA2 functional assays 1.1.0 - Variants assigned with BS3 code in light blue, PS3 code in dark cyan, or no code assigned in black. Mouseover on items show variant HGVS nomenclature, assigned ACMG code and code weight.
• BRCA1/BRCA2 splicing 1.1.0 - Items show variant positions, red indicates exon deletions, blue exon duplications, purple items indicate variants with supporting RNA-based functional evidence. Mouseover on items show transcript, exon, variant position, possible variant type at that position and assigned ACMG code to the variant.
• BRCA1/BRCA2 likelihood for PP4 and BP5 - Variants assigned with PP4 code in brown, BP5 code in orange, and non-informative variants (no code assigned) in grey. Mouseover on items show variant HGVS nomenclature, combined likelihood ratio (LR) score, and assigned ACMG code and strength.

Data Access

The most up-to-date VCEP specifications for application of ACMG/AMP criteria for BRCA1 and BRCA2 genes are freely available at the ClinGen Criteria Specification (CSpec) Registry. This registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

Methods

These data were created and adapted from the files referenced above. Some custom scripting was employed in tasks like mapping variants, adding colors and mouseovers, and producing the desired format.

The multifactorial likelihood analysis scores were recomputed from Parsons et al. 2019 suppl table HUMU-40-1557-s001_Parson_Multicatorial.xlsx, as well as data from Caputo et al 2021, Li et al 2020, and Easton et al 2007. Variants present in both Parsons and Easton were removed from one dataset as as to only be counted once. All likelihood ratios of each matching type (Family LR, Co-occurence LR, segregation LR, pathology LR, and case control LR) were multiplied together and finally those values were then multiplied to create a combined LR score for the variant. For track creation all values were rounded to three decimal places. All individual scores can be seen in the item description page.

For the complete details on the data processing see the makedoc on GitHub.

Credits

Thank you to Luis Nassar from the Genome Browser team, Anna Benet-Pagès, Melissa Cline, and Andreas Laner for technical coordination and consultation, and to the ENIGMA consortia for making these data available.

References

Enigma Guidelines: https://clinicalgenome.org/affiliation/50087/

Enigma Consortium: https://enigmaconsortium.org/

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967; PMC: PMC6772163

Caputo SM, Golmard L, Léone M, Damiola F, Guillaud-Bataille M, Revillion F, Rouleau E, Derive N, Buisson A, Basset N et al. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach. Am J Hum Genet. 2021 Oct 7;108(10):1907-1923. PMID: 34597585; PMC: PMC8546044

Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, Tavtigian SV, Monteiro AN, Iversen ES, Couch FJ et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331; PMC: PMC2265654

Li H, LaDuca H, Pesaran T, Chao EC, Dolinsky JS, Parsons M, Spurdle AB, Polley EC, Shimelis H, Hart SN et al. Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort. Genet Med. 2020 Apr;22(4):701-708. PMID: 31853058; PMC: PMC7118020