Table 3.

Association between seven heterozygous missense variants in six candidate genes and small intestinal neuroendocrine tumors (SI-NETs).

				Variant effect prediction			Minor allele frequency (MAF) in control cohorts			MAF in germline of SI-NET patients compared to the EpiHealth (two-tailed Fisher’s exact test)e				MAF in germline and/or tumor of SI-NET patients compared to the EpiHealth (two-tailed Fisher’s exact test)e
rsID	Gene	cDNA	Amino acid residue change	SIFT	Polyphen	Mut.Taster	1000G (EUR) MAFa	Exac 0.3 (EUR) MAFb	EpiHealth controls MAFc,d	SI-NETs MAF (germline)c	OR	95% CI	P-Value	SI-NETs MAF (cancer+germline)c	OR	95% CI	P-Value
rs61748181	TERT	C/T	p.(Ala279Thr)	Tolerated	Probably damaging	Disease causing	0.036	0.05	0.036 (167/4636)	0.028 (9/316)	0.76	0.35–1.55	0.64	0.027 (12/444)	0.74	0.37–1.35	0.42
rs34635677	SDHA	A/T	p.(Asp38Val)	Tolerated	Benign	Polymorphism	0.032	0.044	0.034 (157/4636)	0.032 (10/316)	0.93	0.43–1.78	1	0.035 (16/458)	1	0.57–1.75	0.89
rs33927012	SDHB	T/C	p.(Ser163Pro)	Tolerated	Benign	Disease causing	0.017	0.015	0.02 (96/4636)	0.013 (4/316)	0.6	0.16–1.62	0.41	0.011 (5/460)	0.52	0.16–1.26	0.22
rs11214077	SDHD	A/G	p.(His50Arg)	Tolerated	Probably damaging	Disease causing	0.017	0.01	0.01 (46/4636)	0.013 (4/318)	1.27	0.33–3.51	0.56	0.011 (5/460)	1.1	0.34–2.77	0.8
rs34677591	SDHD	G/A	p.(Gly12Ser)	Tolerated	Benign	Disease causing	0.01	0.01	0.008 (36/4636)	0.009 (3/318)	1.22	0.24–3.88	0.74	0.007 (3/460)	0.84	0.16–2.67	1
rs36053993	MUTYH	G/A	p.(Gly396Asp)	Damaging	Probably damaging	Disease causing	0.009	0.004	0.003 (12/4636)	0.016 (5/316)	6.19	1.7–19.02	0.0034	0.013 (6/460)	5.09	1.56–14.74	0.0038
rs104893751	OGG1	G/A	p.(Arg46Gln)	Damaging	Probably damaging	Disease causing	0.002	0.003	0.005 (22/4636)	0.01 (3/314)	2.02	0.39–6.79	0.2	0.009 (4/460)	1.84	0.46–5.45	0.29

^aAllele frequencies in this column are based on the European (Non-Finnish) fraction of the 1000 Genomes project, consisting of 503 subjects; ^ballele frequencies in this column are based on the European (Non-Finnish) fraction of the Exac Aggregation Project, consisting of 33,370 subjects; ^cminor allele frequencies (MAFs) were calculated for control and case cohorts by dividing the the number of minor alleles detected by all possible alleles in the population tested. These numbers are reported in parenthesis under the MAFs. The numbers for patients affected with the disease include 15 families, counted as one subject per family affected with SI-NET. Thus, the familial cases add a maximum of 30 alleles to the calculations of MAF in the cohort of patients affected with SI-NETs; ^dthe control cohort used for calculations was the Swedish EpiHealth study; composed of 2318 individuals with the same genetic background as the affected subjects; ^evariants were tested for statistical significance by comparing their prevalence in germline or in germline and/or tumor of affected subjects to their frequency in the EpiHealth. Subjects diagnosed with any typer of cancer were excluded from the EpiHealth cohort before analysis. A two-tailed Fisher’s exact test was used on 2 × 2 contingency tables containing allele MAFs of cases and controls to obtain odds ratios (ORs), 95% confidence intervals (CIs) and P values for each comparison. No correction for multiple testing has been done, since only one test was significant (p.(Gly396Asp) in MUTYH and the P value was very small.