GeneticsTier 1Medical Sciences concept

Assessing variant pathogenicity (conservation, population allele frequency, amino acid change type)

Core concept

A novel genetic variant is classified using multiple converging lines of evidence, not any single feature alone -- the exam tests recognising which pieces of evidence point toward pathogenic vs benign
Population allele frequency: a variant common in population databases (e.g. gnomAD) is evidence against pathogenicity for a rare disease -- disease-causing variants for rare severe conditions should be rare/absent in the healthy population
Evolutionary conservation: a variant at a position highly conserved across species is more likely functionally important -- change there is more likely damaging than at a poorly-conserved position

Type of amino acid change: nonsense (premature stop) and frameshift variants are more likely pathogenic (truncated/absent protein) than missense (single amino acid substitution, effect depends on chemical similarity of the substituted residue) or synonymous (no amino acid change, usually benign unless it disrupts splicing)
Functional domain location: a missense change within a known critical functional domain (e.g. catalytic site, DNA-binding domain) carries more weight than one in a non-critical region
Segregation with disease in the family and de novo occurrence (present in an affected child, absent in both unaffected parents) are strong supporting evidence, independent of the sequence-level features above

Standard classification (ACMG-style framework) combines these lines of evidence into categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, benign -- a VUS should not be used to guide clinical management or family screening until reclassified
Trap: treating a VUS as if it were a confirmed pathogenic finding -- premature action (e.g. prophylactic surgery, cascade family testing) on a VUS is inappropriate
In silico prediction tools (e.g. conservation/structure-based algorithms) provide supporting, not definitive, evidence -- always considered alongside population frequency and segregation data, never in isolation

Directly parallels the somatic vs germline mutation distinction -- pathogenicity assessment applies to germline variants for heritable disease risk, with different implications if found somatically
Splice-site variant assessment (frame/length effect) is a specific sub-case of "type of change" assessment covered in more depth separately
Feeds into genetic counselling: a reclassified VUS (upgraded to likely pathogenic, or downgraded to likely benign) can change management retrospectively -- a reason genetic testing labs periodically re-review historic results

3 more sections, plus exam facts

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