Clinical Variant Analysis: Part III

Clinical Variant Analysis – Classification Criteria of Benign Variants

The classification of benign variants is overall simpler and more straightforward, with the majority of benign variants being eliminated through allele frequency in various population catalogs.

BA1 If a variant is common in one or more population catalog, as indicated by the allele frequency associated by the appropriate sub-population, it can be assumed to be benign. While the ACMG guidelines recommend an allele frequency threshold of 5%, other authors have found that a much lower threshold is more appropriate. For instance, Nykamp et al. (5) found that 97.3% of pathogenic variants had allele frequencies of less than 0.01%. They recommend a threshold of 0.5% for dominant genes and a threshold of 1% for recessive genes.

BS1 If a variant’s allele frequency does not meet the threshold for BA1, but its frequency is still greater than expected for the observed disorder, then BS1 should be applied. Kelly et al. (14) found that a threshold of 0.02% was sufficient for this criterion.

BS2 This criterion is applied if the disease is fully penetrant at an early age and the mutation is observed in a well-documented healthy adult for a dominant (heterozygous), recessive (homozygous), or X-linked (hemizygous) condition.

BS3 Well-established in vitro or in vivo functional studies showing that a variant has no damaging effect on protein function or splicing are considered strong evidence for a benign classification.

BS4 Lack of segregation of a variant with a disease is strong evidence for a benign classification. However, careful evaluation is necessary to rule out the occurrence of the disease in self-reported, unaffected individuals who may have mild symptoms of the disorder. As with PS2, the ACMG guidelines recommend confirmation of family relationships.

BP1 In genes for which LoF variants are the only known mechanism of pathogenicity, missense variants are be considered supporting evidence for a benign classification.

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