Table 3 Genes not selected for secondary findings (SF) list v3.0 and reasoning.
Gene–phenotype | Category | Additional comments |
---|---|---|
Technical concerns | ||
EPCAM-associated Lynch syndrome | Cancer | Concern that deletions or duplications would be difficult to detect by NGS |
GREM1-related polyposis | Cancer | Concern that duplication would be difficult to detect with NGS and overall limited information about this gene |
HNF1B-related maturity-onset diabetes of the young (MODY5) | Miscellaneous | Accounts for ~5% of known MODY with ~50% of cases associated with deletions difficult to detect on exome sequencing |
SDHA/hereditary paraganglioma/pheochromocytoma | Cancer | Concerns about presence of many pseudogenes that could lead to false positive results that would require labs to perform extensive validation work |
Penetrance concerns | ||
BRIP1/RAD51C/RAD51D-related ovarian cancer | Cancer | Lack of effective surveillance modalities for ovarian cancer also a consideration |
DICER1-associated tumors | Cancer | Challenges in DICER1 missense variant interpretation |
HFE-related hemochromatosis (except for HFE p.C282Y homozygotes) | Miscellaneous | Penetrance is driven by the p.Cys282Tyr variant, and not other variants in HFE |
TTR-amyloidosis | Miscellaneous | Also considered that sudden death was rare, thus allowing time for clinical diagnosis |
Clinical management concerns | ||
ABCD1 X-linked adrenoleukodystrophy | IEM | Severe cases have early onset and would be diagnosed by newborn screening; no specific treatment in adulthood |
BAP1-related tumors | Cancer | Small number of families reported to date and no established consensus management recommendations as of time reviewed |
COL5A1-associated Ehlers–Danlos syndrome | Miscellaneous | Not considered highly actionable |
GCH1-related dopa-responsive dystonia | Miscellaneous | Concern that diagnosis of the classic phenotype is relatively straightforward and that the treatment efficacy was not dependent on the timing of initiation |
HMBS-associated acute intermittent porphyria | Miscellaneous | Concern that avoidance of exposures and delays in diagnosis could be out of scope for the ACMG SF list |
MEFV-associated familial Mediterranean fever | Miscellaneous | Concern about clinical management of acute episodes being primarily supportive, and diagnosis could then be made through diagnostic testing |
NOTCH3/CADASIL | Miscellaneous | Not considered highly actionable |
POLD1/POLE-related polyposis | Cancer | Rarity of known pathogenic variants that could be reported and uncertain risks of extracolonic cancers |
PRKAR1A/Carney complex | Miscellaneous | Concerns about penetrance and questions about actionability |
SERPINA1-related alpha-1-antitrypsin deficiency | Miscellaneous | Concern that avoidance of exposures could be out of scope for the ACMG SF list |