ABMGG LGG common mistakes
ABMGG LGG · Understand the traps and how to avoid them.
Reading a cytogenomic microarray report and calling an isolated copy-number variant pathogenic without first checking whether the interval is a known benign CNV, a region of common variation, or fully penetrant in the population databases.
Candidates anchor on the size of the deletion/duplication and the gene content, forgetting that many recurrent CNVs are inherited from an unaffected parent or are documented benign population variants; the urge to 'call something' overrides the ACMG/ClinGen CNV scoring framework.
What to do instead
Apply a structured CNV classification: check ClinGen dosage sensitivity, DECIPHER, gnomAD-SV, and parental inheritance before assigning a tier. Practice scoring a variant against each ACMG/ClinGen CNV criterion explicitly and document which criteria are met, unmet, or not applicable.
Classifying a missense variant as likely pathogenic primarily because in-silico predictors (SIFT, PolyPhen, CADD) flag it, treating computational evidence as strong rather than supporting.
Predictors are easy to run and give a numeric score, so candidates overweight them; they forget that ACMG/AMP code PP3/BP4 is capped at supporting strength and cannot by itself move a variant past VUS.
What to do instead
Memorize the strength ceiling for each ACMG code (PP3/BP4 = supporting only) and practice building a classification where computational evidence is one line among many. When only PP3 is present with no other evidence, the correct call is VUS, and candidates should be able to defend that.
Misinterpreting a variant of uncertain significance as actionable in a clinical report or counseling scenario, recommending surveillance or family testing as if it were pathogenic.
Candidates conflate 'we found a variant' with 'we found the cause'; the pressure to provide closure to a family pushes them to over-interpret. They also confuse segregation in an affected relative with proof of causality.
What to do instead
Practice writing VUS language that explicitly states the variant does not explain the phenotype and that management should follow phenotype-based guidelines. Drill the distinction between 'reportable' and 'actionable' and rehearse the counseling script for a VUS disclosure.
Failing to recognize when a biochemical or enzymatic assay result is confounded by sample type, timing, or treatment, and interpreting it at face value.
Candidates treat a single abnormal metabolite or enzyme level as diagnostic without considering preanalytical variables (fasting, hemolysis, transfusion history, enzyme replacement therapy) that the vignette deliberately embeds.
What to do instead
Before interpreting any biochemical result, systematically list preanalytical confounders for that analyte. Build a one-page confounder table per disorder class (lysosomal storage, aminoacidopathy, organic acidemia) and practice identifying the distractor in vignettes.
Choosing the wrong confirmatory test after an abnormal newborn screen (e.g., ordering molecular testing first when a biochemical confirmatory assay is the standard of care, or vice versa).
Candidates memorize the screening abnormality but not the diagnostic algorithm; they also over-rely on sequencing because it feels definitive, ignoring that enzyme assay or metabolite quantification is often the confirmatory standard.
What to do instead
For each NBS condition on the differential, write the two-step pathway: screening analyte abnormality → confirmatory test → molecular confirmation if indicated. Drill the specific exceptions where molecular testing is the confirmatory first step (e.g., CF, SMA, hemoglobinopathies).
Misreading a karyotype or FISH result by miscounting chromosome number, missing a subtle structural rearrangement, or misassigning breakpoints in an unbalanced translocation.
Candidates skim the ISCN string and rely on the impression rather than parsing each band; they also confuse derivative chromosomes with the original chromosome in unbalanced rearrangements.
What to do instead
Practice parsing ISCN nomenclature character by character and reconstructing the karyotype from the string. For translocations, explicitly identify which chromosome is the derivative and whether the imbalance is gain or loss before answering.
Applying population-based carrier frequency or Bayesian residual-risk calculations using the wrong prior (e.g., using the general population carrier rate for an individual with an affected sibling, or forgetting to adjust for ethnicity-specific frequencies).
Candidates know the formula but pick the wrong prior probability, or they forget that family history, consanguinity, and ethnicity change the prior; arithmetic slips compound the error.
What to do instead
Practice a set of residual-risk problems where the key step is identifying the correct prior from the pedigree and the correct carrier frequency from the stated ethnicity. Write out the Bayesian table explicitly rather than doing it mentally.
Failing to distinguish somatic from germline findings in tumor profiling, or misinterpreting variant allele fraction and tumor purity when deciding whether a variant is constitutional.
Candidates treat any variant in a tumor report as somatic, or conversely over-call germline based on a single VAF without accounting for tumor cellularity and copy number.
What to do instead
For tumor variants, state the expected VAF for germline heterozygous (~50% adjusted for purity), somatic heterozygous, and homozygous loss, and check whether the observed VAF fits. Practice deciding when germline confirmation on a normal sample is indicated.
Misinterpreting methylation or imprinting test results by ignoring the tissue tested, the assay's ability to distinguish imprinting-center defects from UPD, and the possibility of a mosaic or tissue-limited finding.
Candidates memorize 'abnormal methylation = imprinting disorder' without knowing that methylation testing cannot distinguish the molecular mechanism, and they forget that blood may not reflect the relevant tissue.
What to do instead
For each imprinting disorder, build a mechanism table (deletion, UPD, IC epimutation, single-gene variant) and note which test distinguishes which. Practice choosing the next test after an abnormal methylation result to define the mechanism.
Answering a management or counseling question with the test result alone, omitting the downstream actions (referral, surveillance, reproductive options, family cascade testing) that the question is actually testing.
Candidates stop at the diagnosis because the genetics is the interesting part, but these items are written to test the full clinical pathway; they also forget that cascade testing and reproductive counseling are part of the answer.
What to do instead
For every diagnosis, rehearse a standard four-part answer: confirmation, management/surveillance, reproductive counseling, and family cascade testing. Practice identifying which of these the question stem is actually asking for before selecting.