Assessing pathogenicity according to international standards
DECIPHER supports the annotation and sharing of variant pathogenicity
using ACMG guidelines for sequence variants and ACMG/ClinGen technical
standards for CNVs, which helps to standardise the classification of
variants across centres. When interpreting a CNV it is possible for
users to choose to assess the variant using sequence variant guidelines,
which may be more applicable for small CNVs since the distinction
between a sequence variant and a CNV is blurred (Brandt et al .,
2019).
Criteria selection: In both pathogenicity interfaces (Fig. 5A,
5B), types of evidence (such as population data and functional data) are
displayed, along with the relevant evidence criteria used to determine
if data supports the variant being pathogenic or benign. Relevant
criteria can be selected with a single click. Some of the criteria have
additional information links. These either provide information about how
the criteria can be used according to the original paper (e.g. de
novo CNV evidence), or in the case of sequence variants they provide
information about ClinGen Sequence Variant Interpretation (SVI) Working
Group guidelines (e.g. recommendation for functional assays (PS3/BS3)
Brnich et al ., 2019). As new guidelines become available these
pathogenicity interfaces are updated to provide the latest relevant
recommendations. Criteria strengths can be modified as required in the
interface.
Relevant evidence: Within the interfaces there is a customised
section displaying ‘evidence to consider’ which provides information
relating to the specific evidence type being assessed. For example, for
computational and predictive data evidence, predictive pathogenicity
scores (SIFT, PolyPhen-2, CADD, REVEL, SpliceAI) are displayed. Links
are also provided to relevant DECIPHER interpretation interfaces, for
example to the in-built tolerated population variation calculator, which
can be used to determine if a variant observed in the reference sample
is too common to cause a given Mendelian disorder of interest (Whiffinet al ., 2017). External links (e.g. PubMed literature search) are
also provided.
Calculation of variant pathogenicity: As criteria are added,
DECIPHER uses these to calculate the variant pathogenicity. For sequence
variants, this is calculated according to the combining rules detailed
in the original 2015 ACMG guidelines. In addition, DECIPHER calculates
the posterior probability of pathogenicity and classification according
to the ClinGen SVI Working Group’s Bayesian classification framework,
which provides a mathematical foundation for the combining rules
(Tavtigian et al ., 2018). DECIPHER highlights cases where these
classifications disagree, and ultimately all pathogenicity assessments
are made by depositors using their professional discretion. For CNVs,
the evidence can be scored according to ACMG/ClinGen technical standards
instead.
ClinGen Expert Panel specifications: For some genes there are
ClinGen Variant Curation Expert Panel Specifications, which recommend
adaptations of the sequence variant ACMG guidelines (e.g. Rett and
Angelman-like Disorders Variant Curation Expert Panel for MECP2 ,CDKL5 , FOXG1 , UBE3A , SLC9A6, andTCF4 ). When interpreting variants in genes for which these
recommendations exist, detailed information about how to apply the
criteria is provided along with a link to the relevant Clinical Domain
Working Group, so that patients with variants in these genes benefit
from interpretation in accordance with these recommended standards.