Table 2. Incidental findings with potentially actionable consequences.

Incidental finding condition	Gene	AA change	UK10K	EVS_EA	Comments
I. Reportable Incidental Findings
Arrhythmogenic right ventricular cardiomyopathy (ARVC)	DSG2	NM_001943: c.2397T>G:p.Y799*	absent	absent	Stop gain mutation, not previously reported, but mutation class considered pathogenic44
	DSG2	NM_001943: c.2554G>T:p.E852*	absent	absent	As above
Breast & ovarian cancer	BRCA2	NM_000059: c.7558C>T:p.R2520*	absent	0.0001	Stop gain mutation; 5 independent R2520* in affected patients45-49. 4 reports of variant being pathogenic in ClinVar50 (submitted by independent clinical labs) and 7 records rated as causal in UMD-BRCA2 database51. Mutations of this class described in Brohet, et al. 52.
Long QT syndrome	KCNQ1	NM_000218: c.877C>T:p.R293C	absent	absent	2 independent reports in literature: i) 4 /2500 independent cases from FAMILION cohort referred for LQT genetic testing53 and ii) 1 case /388 consecutive unrelated patients with swimming triggered arrhythmia syndromes54, as compound heterozygote with G269D. Location of mutation in pore suggestive of pathogenicity.
II. Incidental Findings of Uncertain Significance
Long QT syndrome	KCNQ1	NM_000218: c.1189C>T:p.R397W	absent	0.0006	3 independent reports in literature, including 3/2500 independent cases referred for long QT testing55, 5/600 cases in LQT registry53 and 1/91 independent cases of intrauterine foetal death56. Functional data from heterologous expression of mutation i) in HEK293 cells which shows markedly reduced current on whole cell patch clamp compared with WT56 and ii) in inside-out membrane patches from Xenopus oocytes which showed markedly reduced ATP binding57. Taken together, this suggests that the mutation should not be disregarded clinically as it may be weakly pathogenic, albeit with low absolute risk
Malignant hyperthermia	RYR1	NM_000540: c.5036G>A:p.R1679H	0.0006	0.0014	Variant observed in single subject with complication, and positive functional testing58 but no independent replication.

Variants deemed to be reportable and clinically actionable are listed Section I of the table. Those for which the evidence was not considered sufficient to be clinically actionable are reported or are uncertain are listed in Section II.

AA: amino acid; VUS: variant of unknown significance; UK10K: frequency in the UK10K twin cohort; EVS: Exome Variant Server; EVS_EA: frequency in European Americans in the EVS; HGMD: Human Gene Mutation Database; UMD: Universal Mutation Database (see URLs).