Glossary of genetic-diagnostics terms

Glossary

Roughly sixteen terms that recur across the swab-to-sequencer pathway. Definitions are concise on purpose; the linked guides go deeper.

Allele

One of the alternative forms of a gene or DNA sequence at a given position. Humans carry two alleles at most locations — one inherited from each parent. A hereditary-cancer variant usually affects a single allele (heterozygous), which can be enough to raise risk.

BRCA1

A tumour-suppressor gene on chromosome 17. Carriers of a pathogenic BRCA1 variant have an estimated cumulative breast-cancer risk of roughly 55–65% by age 70 and an ovarian-cancer risk reported up to ~44%, well above general-population baselines. Its counterpart BRCA2 confers a similar but generally somewhat lower profile.

Germline vs somatic

A germline variant is present in the egg or sperm and therefore in (nearly) every cell from birth — it is heritable and is what hereditary-cancer registries study. A somatic variant is acquired in a tumour during life and is not passed to children. Sample type matters: blood and saliva yield germline DNA; tumour tissue yields somatic.

Penetrance

The proportion of people carrying a particular variant who actually develop the associated condition by a given age. Penetrance is rarely 100%; it is the central quantity the PROMPT Registry was built to refine for less-characterised, moderate-risk genes.

Pathogenic

The highest-confidence ACMG/AMP tier for a disease-causing variant — proposed to correspond to ~99% certainty that the change is harmful. "Likely pathogenic" sits at ~90% certainty. Both are typically actionable; the benign tiers are not.

VUS

Variant of uncertain significance — a change whose effect on disease risk is not yet established (the middle of the five ACMG/AMP tiers). A VUS should generally not drive medical action on its own; many are later reclassified up or down as evidence accumulates, which is exactly what multi-institution registries accelerate.

ACMG

The American College of Medical Genetics and Genomics. Its 2015 joint framework with the AMP set the five-tier system — benign, likely benign, VUS, likely pathogenic, pathogenic — combining 28 evidence criteria across population, computational, functional and segregation data.

Founder variant

A specific pathogenic variant that is unusually common in a population because it descends from a shared ancestor — for example, well-described BRCA1/BRCA2 founder variants in some Ashkenazi Jewish families. Founder effects can simplify targeted testing within a population.

Multiplex (multi-gene) panel

A single test that sequences many cancer-susceptibility genes at once rather than one gene at a time. The "M" in PROMPT — Prospective Registry of Multiplex Testing — refers to exactly this shift, which surfaced more variants in less-studied genes and created the need to estimate their penetrance.

NGS

Next-generation sequencing — massively parallel sequencing that reads millions of DNA fragments at once. Clinical germline cancer panels commonly run at >300× mean read depth with a floor around 100× per base, balancing sensitivity against cost.

Sanger sequencing

The older, single-amplicon chain-termination method. Highly accurate but low-throughput, it is now used mainly to confirm individual pathogenic/likely-pathogenic calls from an NGS panel — an orthogonal check, though high-depth NGS increasingly stands on its own.

Biospecimen

The biological sample submitted for testing — saliva, a buccal (cheek) swab, or whole blood. Choice of biospecimen drives DNA yield and stability: stabilised saliva in a kit such as OG-500 can remain stable at room temperature for years, whereas blood typically needs cold-chain handling.

Genetic counsellor

A specialist clinician trained to assess family history, explain testing options, interpret results in context, and support decision-making. Registries and explainers signpost a counsellor precisely because a report — especially a VUS — needs personal interpretation that a glossary cannot give.

Registry

A structured, longitudinal collection of de-identified participant and variant data used for research. The PROMPT Registry pooled multiplex-testing results across institutions (MSKCC, Penn, Mayo and partner laboratories) to study penetrance in rarer hereditary-cancer genes — a heritage of collaborative evidence, not an enrolling clinical service.

rs identifier

A stable reference-SNP accession (for example rs80357906) assigned in public databases so the same variant can be cited unambiguously across laboratories and papers — the variant-level equivalent of a gene symbol.

Biospecimens at a glance

The collection step quietly shapes everything downstream — yield, stability, and how a sample must be packed and shipped. Representative figures from manufacturer specifications and the diagnostics literature.

Table 1. Common germline biospecimens for hereditary-cancer testing (representative values; consult the laboratory's own protocol).

Why penetrance, not just presence, drives counselling

Carrying a variant is not the same as certain disease. Approximate cumulative cancer risks by ~age 70 for high-penetrance BRCA carriers against general-population baselines — the gap a counsellor helps interpret.