For detailed description see Table 5 in Richards et al, 2015

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Benign Pathogenic
Strong Supporting Stand Alone Supporting Moderate Strong Very Strong
Population Data MAF is too high for disorder. BS1
OR
observation in controls inconsistent with disease penetrance BS2 		BS1-Supporting
BS2-Supporting 		MAF is too high for disorder BA1 PM2-Supporting
PS4-Supporting 		Absent in population databases PM2

PS4-Moderate 		Prevalence in affecteds statistically increased over controls PS4

PM2-Strong 		PM2-Very Strong
PS4-Very Strong
Computational And Predictive Data BP4-Strong
BP1-Strong
BP7-Strong
BP3-Strong 		Multiple lines of computational evidence suggest no impact BP4
Missense when only truncating cause disease BP1
Silent variant with non predicted splice impact BP7
In-frame indels in repeat w/out known function BP3 		Multiple lines of computational evidence support a deleterious effect on the gene /gene product PP3

PM4-Supporting
PM5-Supporting
PS1-Supporting
PVS1-Supporting 		Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before PM5.
Protein length changing variant PM4

PP3-Moderate
PS1-Moderate
PVS1-Moderate 		Same amino acid change as an established pathogenic variant PS1

PP3-Strong
PM4-Strong
PM5-Strong
PVS1-Strong 		Predicted null variant in a gene where LOF is a known mechanism of disease PVS1

PS1-Very Strong
PM4-Very Strong
PM5-Very Strong
PP3-Very Strong
Functional Data Well-established functional studies show no deleterious effect BS3 BS3-Supporting Missense in gene with low rate of benign missense variants and path. missenses common PP2

PM1-Supporting
PS3-Supporting 		Mutational hot spot or well-studied functional domain without benign variation PM1

PP2-Moderate
PS3-Moderate 		Well-established functional studies show a deleterious effect PS3

PM1-Strong
PP2-Strong 		PP2-Very Strong
PM1-Very Strong
PS3-Very Strong
Segregation Data Non-segregation with disease BS4 BS4-Supporting Co-segregation with disease in multiple affected family members PP1 PP1-Moderate PP1-Strong PP1-Very Strong
De novo Data PM6-Supporting
PS2-Supporting 		De novo (without paternity & maternity confirmed) PM6

PS2-Moderate 		De novo (paternity & maternity confirmed) PS2

PM6-Strong 		PM6-Very Strong
PS2-Very Strong
Allelic Data BP2-Strong Observed in trans with a dominant variant BP2
Observed in cis with a pathogenic variant BP2 		PM3-Supporting For recessive disorders, detected in trans with a pathogenic variant PM3 PM3-Strong PM3-Very Strong
Other Databases BP6-Strong Reputable source w/out shared data = benign BP6Controversial Reputable source = pathogenic PP5 Controversial PP5-Moderate PP5-Strong PP5-Very Strong
Other Data BP5-Strong Found in case with an alternate cause BP5 Patient’s phenotype or FH highly specific for gene PP4 PP4-Moderate PP4-Strong PP4-Very Strong