Guidelines

Reference framework classifying variants into 5 tiers (pathogenic to benign) from weighted criteria.

Forthcoming joint standard subdividing VUS by likelihood of pathogenicity (VUS-low / -mid / -high) via a Bayesian point-based system. In pilot phase, not yet finalised.

Calibrated thresholds for computational tools (REVEL ≥ 0.7 / ≤ 0.3…) to apply the PP3/BP4 criteria.

Points-based scoring system to classify copy-number variants and harmonise classification across laboratories.

Grades the strength of a gene-disease link (Definitive → Refuted) — useful before adding a gene to a diagnostic panel.

Genes to report as secondary findings (actionable P/LP variants) in exome/genome sequencing; ABCD1, CYP27A1, PLN added.

Cautious European stance: proportionality, autonomy and the right not to know regarding secondary findings.

Strong recommendation: exome/genome sequencing as first- or second-line test in children with congenital anomalies or intellectual disability.

Genome sequencing via the national platforms for HAS-validated rare-disease and cancer-predisposition pre-indications.

Carrier screening (113 genes, Tier 3) to offer at preconception or in pregnancy for autosomal-recessive and X-linked conditions.

Non-invasive prenatal screening for T21 from cell-free fetal DNA; opportunity to extend to other aneuploidies (Oct 2024).

Prenatal fetal exome: as a trio, after validation, with pre/post-test counselling — not routine.

Restrict analysis to the original health problem; consent and disclosure framework for genome sequencing.

French recommendations: 13-gene panel of validated clinical utility (BRCA1/2, PALB2, TP53, CDH1, PTEN, RAD51C/D, MMR genes, EPCAM).

Gene-specific ACMG/AMP criteria for BRCA1/BRCA2 (ClinGen ENIGMA expert panel, calibrated evidence strengths).

International reference: genetic-testing criteria and management of hereditary cancer predispositions.

French reference database (frog-db.fr): harmonised classification of predisposition-gene variants, validated by GGC expert groups.

Surveillance and risk-reducing surgery in BRCA1/2 carriers (e.g. RRSO at 35-40 y for BRCA1, 40-45 y for BRCA2).

French early-detection (breast, adnexa) and risk-reduction recommendations, accounting for carrier radiosensitivity.

Identification of germline TP53 variant carriers and multimodal surveillance (including whole-body MRI).

European guidelines (3rd 'Mallorca' edition): colonoscopic surveillance and management by MMR gene and sex.

Prophylactic total gastrectomy recommended in CDH1 carriers; endoscopic surveillance in expert centres as an alternative.

Cancer-predisposition genes (BRCA1/2, MMR, TP53, APC…) form a major part of the secondary-findings list to report in exome/genome sequencing.