Rare variants with potential health impact identified in the study, by participant ID no.
| Participant ID no. | Gene (accession no.) | Variant, zygosity | Associated disease, inheritance | Interpretation: evidence* | Clinical follow-up | Management implications |
|---|---|---|---|---|---|---|
| PGPC-43 | BRCA1‡ (NM_007300.3) | c.68_69delAG, p.(Glu23Valfs*17), het | Breast and ovarian cancer, AD | Pathogenic: PVS1, PS3, PS4, PP520 | FHx of prostate cancer (70–80 yr) | 1, 2, 3 |
| PGPC-16† | ELN (NM_001278914.1) | c.455–1G > A, p.?, het | Supravalvular aortic stenosis, AD | Likely pathogenic: PVS1, PM221 | No relevant PHx/FHx, normal heart CT | 1, 2, 3 |
| PGPC-25† | LMNA§ (NM_170707.3) | c.1748C > T, p.(Ser583Leu), het | Lipodystrophy, familial partial, AD/AR | Likely pathogenic: PM1, PM2, PP1, PP322 | PHx of hypercholesterolemia, hyperpigmented patch | 1, 2, 3 |
| PGPC-16† | LZTR1 (NM_006767.3) | c.774delT, p.(Phe258Leufs*93), het | Schwannomatosis, AD | Likely pathogenic: PVS1, PM223 | No relevant PHx/FHx | 1, 2, 3 |
| PGPC-40† | SLC7A9 (NM_001243036.1) | c.614dupA, p.(Asn206Glufs*3), het | Cystinuria, AD/AR | Pathogenic: PVS1, PS4-M, PP524,25 | No relevant PHx/FHx | 1, 2, 3 |
| PGPC-27† | Multiple | Seq[GRCh37] Xp22.33q28(1_155270560)x1[0.7] | Mosaic Turner syndrome | Pathogenic26 | No obvious clinical manifestation | 1, 2 |
| PGPC-02, PGPC-27† | CHEK2 (NM_145862.2) | c.470T > C, p.(Ile157Thr), het | Cancer susceptibility, AD/AR | Risk factor: PS4, PP527,28 | 27: FHx of breast, prostate, throat cancer | 1, 2, 3 |
| PGPC-25,† PGPC-29 | F2 (NM_000506.3) | c.*97G > A (20210G > A), het | Thrombophilia, AD/AR | Risk factor: PS3, PS429 | 29: No relevant PHx/FHx | 1, 2, 3 |
| PGPC-24 | LPL (NM_000237.2) | c.953A > G, p.(Asn318Ser), het | Dyslipidemia, AD/AR | Risk factor: PS3, PS430–32 | PHx/FHx of hypercholesterolemia, FHx of CAD (60 yr) | 1, 2, 3 |
| PGPC-36 | MUTYH¶ (NM_001048171.1) | c.892–2A > G, p.?, het | Familial adenomatous polyposis, AR; colorectal cancer risk, AD | Risk factor (AD), pathogenic (AR): PVS1, PS3, PP5, BS133,34 | FHx of gastric cancer (70–80 yr) | 1, 2, 3 |
| PGPC-48 | PCDH15 (NM_001142769.1) | chr10:g. [55741501_57660800del], het (1.9 Mb) | Neuropsychiatric disease risk, AD; deafness/Usher syndrome, AR | Risk factor (AD), likely pathogenic (AR): PVS1, PM235–38 | FHx of ADHD | 1, 3 |
| Variants of uncertain significance | ||||||
| PGPC-40† | ANK2 (NM_001148.4) | c.4373A > G, p.(Glu1458Gly), het | Long QT syndrome, cardiac arrhythmia, AD | VUS: PS3, PP1, BS139–41** | No relevant PHx/FHx | 1, 2 |
| PGPC-40† | CDH1 (NM_004360.3) | c.2343A > T, p.(Glu781Asp), het | CDH1-related cancer, AD | VUS: PM242,43 | FHx of gastric cancer (75–80 yr) | 1, 2 |
| PGPC-19 | CHMP2B (NM_014043.3) | c.85A > G, p.(Ile29Val), het | Amyotrophic lateral sclerosis, Frontotemporal dementia, AD | VUS: PS3, PP5, BP444–46 | No relevant PHx/FHx | 1 |
| PGPC-14 | KCNE2 (NM_172201.1) | c.29C > T, p.(Thr10Met), het | Long QT syndrome, Atrial fibrillation, AD | VUS: PP5, BS147,48 | ND | 1, 2 |
| Uncertain significance, genetic counselling recommended | ||||||
| PGPC-32 | MT-TV | m.1659T > C, 7% heteroplasmy | Childhood neurologic disorder | Likely pathogenic††49 | ND | 1, 4 |
| PGPC-22 | Multiple | Seq[GRCh37] inv(20) (q11.23q13.12), chr20:g. [35583655_44214109inv], het (8.6 Mb) | Likely minimal risk for unbalanced aberrations in family members | Large, rare structural variant | ND | 1 |
| 53 of 56 PGPC participants | 172 recessive carrier variants (e.g., 5 pathogenic CFTR alleles) | Multiple | Potential disease risk in family members | Risk factor | ND | 1, 4 |
Note: AD = autosomal dominant, ACMG = American College of Medical Genetics and Genomics, ADHD = attention-deficit/hyperactivity disorder, AR = autosomal recessive, CAD = coronary artery disease, CT = computed tomography, FHx = family history, het = heterozygous, LEP = limited evidence for pathogenicity, Mb = megabase pairs, ND = no data, PGPC = Personal Genome Project Canada, PHx = personal history, VUS = variant of uncertain significance. Management implications: genetic counselling = 1, screen/monitor for medical complications and anticipate risk prevention = 2, identification of family members at risk = 3, Family planning = 4.
↵* Interpretation according to the ACMG guidelines.16
↵† Participants with 2 or more variants.
↵‡ Gene is included in the ACMG list.50
↵§ Gene is included in the ACMG list but associated to a different phenotype (dilated cardiomyopathy).
↵¶ Gene is included in the ACMG list when biallelic.
↵** This variant was recently interpreted as likely pathogenic in another healthy cohort.51
↵†† Pathogenic at a higher level of heteroplasmy.