CanVIG-UK Consensus Specification

General Guidance Notes:

• Evidence items for which CanVIG-UK has offered additional specification are shaded in grey.  Evidence items are shaded in white where there is no additional specification beyond ACGS Best Practice Guidelines version 4.01 (04/02/2020).

• Gene specific guidance for specific CSGs can be viewed at https://www.cangene-canvaruk.org/gene-specific-recommendations and should be followed for genes where these exist. These include CanVIG-UK gene specific guidance and gene specific guidance from ClinGen Sequence Variant Interpretation (SVI) Working Groups (+/- notes from CanVIG-UK).

• Evidence items can be combined using evidence (exponent) points for evidence towards pathogenicity (Very Strong= 8, Strong= 4, Moderate= 2, Supporting= 1) or towards benignity (Very Strong= -8, Strong= -4, Moderate= -2, Supporting= -1). Thresholds: ≥10 (Pathogenic), 6-9 (Likely Pathogenic), (-1) – (-5) (Likely Benign), ≤-6 (Benign). It is recommended that evidence criteria and evidence (exponent) scores are included on clinical reports.

• ≥2 concordant evidence items are required for a classification of likely pathogenic/pathogenic/likely benign/benign, with the exception of BA1, which provides standalone evidence towards benignity

• Variants should be reported using HGVS nomenclature, including the clinically appropriate transcript and version number (e.g. MANE select and/or MANE clinical plus) and human reference genome build.

• This specification can be used for single nucleotide variants and insertions/deletions of less than a single gene in size. For insertions and deletions of equal or greater than one gene in size, refer to the ACMG CNV guidance.