Table 1 ACMG SF v3.0 gene and associated phenotypes recommended for return as secondary findings from clinical exome and genome sequencing.

From: 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)

Phenotype	ACMG SF list version	MIM disorder	Gene	Inheritance	Variants to report^a
Genes related to cancer phenotypes
Familial adenomatous polyposis	1.0	175100	APC	AD	All P and LP
Familial medullary thyroid cancer	1.0	155240	RET^b	AD	All P and LP
Hereditary breast and/or ovarian cancer	1.0 1.0 3.0	604370 612555 114480	BRCA1 BRCA2 PALB2	AD	All P and LP
Hereditary paraganglioma–pheochromocytoma syndrome	1.0 1.0 1.0 1.0 3.0 3.0	168000 601650 605373 115310 171300 171300	SDHD SDHAF2 SDHC SDHB MAX TMEM127	AD	All P and LP
Juvenile polyposis syndrome	2.0 2.0	174900 175050	BMPR1A SMAD4^c	AD	All P and LP
Li–Fraumeni syndrome	1.0	151623	TP53	AD	All P and LP
Lynch syndrome	1.0 1.0 1.0 1.0	609310 120435 614350 614337	MLH1 MSH2 MSH6 PMS2	AD	All P and LP
Multiple endocrine neoplasia type 1	1.0	131100	MEN1	AD	All P and LP
MUTYH-associated polyposis	1.0	608456	MUTYH	AR	P and LP (2 variants)
Neurofibromatosis type 2	1.0	101000	NF2	AD	All P and LP
Peutz–Jeghers syndrome	1.0	175200	STK11	AD	All P and LP
PTEN hamartoma tumor syndrome	1.0	158350	PTEN	AD	All P and LP
Retinoblastoma	1.0	180200	RB1	AD	All P and LP
Tuberous sclerosis complex	1.0 1.0	191100 613254	TSC1 TSC2	AD	All P and LP
von Hippel–Lindau syndrome	1.0	193300	VHL	AD	All P and LP
WT1-related Wilms tumor	1.0	194070	WT1	AD	All P and LP
Genes related to cardiovascular phenotypes
Aortopathies	1.0 1.0 1.0 1.0 1.0 1.0	154700 609192 610168 613795 611788 132900	FBN1 TGFBR1 TGFBR2 SMAD3 ACTA2 MYH11	AD	All P and LP
Arrhythmogenic right ventricular cardiomyopathy	1.0 1.0 1.0 1.0 1.0	609040 607450 610476 604400 610193	PKP2 DSP^d DSC2 TMEM43 DSG2	AD	All P and LP
Catecholaminergic polymorphic ventricular tachycardia	1.0 3.0 3.0	604772 611938 615441	RYR2 CASQ2 TRDN^e	AD AR	All P and LP P and LP (2 variants)
Dilated cardiomyopathy	1.0 1.0 3.0 3.0	601494 115200 617047 604145	TNNT2^f LMNA FLNC TTN^g	AD	All P and LP See text
Ehlers–Danlos syndrome, vascular type	1.0	130050	COL3A1	AD	All P and LP
Familial hypercholesterolemia	1.0 1.0 1.0	143890 144010 603776	LDLR APOB PCSK9	AD AD	All P and LP
Hypertrophic cardiomyopathy^h	1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0	192600 115197 613690 115196 608751 612098 600858 608758	MYH7^d MYBPC3 TNNI3 TPM1 MYL3 ACTC1 PRKAG2ⁱ MYL2	AD	All P and LP
Long QT syndrome types 1 and 2	1.0 1.0	192500 613688	KCNQ1 KCNH2	AD	All P and LP
Long QT syndrome 3; Brugada syndrome	1.0	603830, 601144	SCN5A^d	AD	All P and LP
Genes related to inborn errors of metabolism phenotypes
Biotinidase deficiency	3.0	253260	BTD	AR	P and LP (2 variants)
Fabry disease	1.0	301500	GLA^j	XL	All hemi, het, homozygous P and LP
Ornithine transcarbamylase deficiency	2.0	311250	OTC	XL	All hemi, het, homozygous P and LP
Pompe disease	3.0	232300	GAA	AR	P and LP (2 variants)
Genes related to miscellaneous phenotypes
Hereditary hemochromatosis	3.0	235200	HFE	AR	HFE p.Cys282Tyr homozygotes only^k
Hereditary hemorrhagic telangiectasia	3.0 3.0	600376 187300	ACVRL1 ENG	AD	All P and LP
Malignant hyperthermia	1.0 1.0	145600 601887	RYR1 CACNA1S	AD	All P and LP
Maturity-onset diabetes of the young	3.0	600496	HNF1A	AD	All P and LP
RPE65-related retinopathy	3.0	204100, 613794	RPE65	AR	P and LP (2 variants)
Wilson disease	2.0	277900	ATP7B	AR	P and LP (2 variants)

AD autosomal dominant, AR autosomal recessive, LP likely pathogenic, P pathogenic, XL X-linked.
^aVariants within genes associated with autosomal dominant phenotypes should be classified as pathogenic or likely pathogenic to be reportable. Genes associated with phenotypes inherited in an autosomal recessive fashion would need two likely pathogenic and/or pathogenic variants (or an apparently homozygous variant) to meet threshold for reporting even when phase is undetermined, as follow-up family variant testing can often resolve phase or confirm homozygosity. Finally, P/LP variants within genes associated with X-linked phenotypes that are apparently hemizygous (hemi), heterozygous (het), compound heterozygous, or homozygous should be reported, as heterozygous females can have adverse medical events at a reasonable frequency and treatment or amelioration of disease is available. Variants of uncertain significance should not be reported in any gene.
^bAlso associated with multiple endocrine neoplasia type 2.
^cAlso associated with hereditary hemorrhagic telangiectasia.
^dAlso associated with dilated cardiomyopathy (DCM) as a primary disease.
^eAlso associated with long QT syndrome.
^fAlso associated with hypertrophic cardiomyopathy (HCM).
^gOnly loss-of-function variants should be reported as a secondary finding.
^hIndividuals with primary HCM may present in late stage disease with a DCM phenotype.
ⁱPathogenic variants in this gene are associated with metabolic storage disease that mimics a HCM, but also can involve skeletal muscle.
^jGene also applies to the cardiovascular category.
^kTranscript for the HFE gene is NM_000410.3.

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Table 1 ACMG SF v3.0 gene and associated phenotypes recommended for return as secondary findings from clinical exome and genome sequencing.

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