Table 3 Genes not selected for secondary findings (SF) list v3.0 and reasoning.

From: Correction to: ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

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

  1. ACMG American College of Medical Genetics and Genomics, IEM inborn errors of metabolism, NGS next-generation sequencing.