Table 3:

Rare variants with potential health impact identified in the study, by participant ID no.

Participant ID no.Gene (accession no.)Variant, zygosityAssociated disease, inheritanceInterpretation: evidence*Clinical follow-upManagement implications
PGPC-43BRCA1 (NM_007300.3)c.68_69delAG, p.(Glu23Valfs*17), hetBreast and ovarian cancer, ADPathogenic: PVS1, PS3, PS4, PP520FHx of prostate cancer (70–80 yr)1, 2, 3
PGPC-16ELN (NM_001278914.1)c.455–1G > A, p.?, hetSupravalvular aortic stenosis, ADLikely pathogenic: PVS1, PM221No relevant PHx/FHx, normal heart CT1, 2, 3
PGPC-25LMNA§ (NM_170707.3)c.1748C > T, p.(Ser583Leu), hetLipodystrophy, familial partial, AD/ARLikely pathogenic: PM1, PM2, PP1, PP322PHx of hypercholesterolemia, hyperpigmented patch1, 2, 3
PGPC-16LZTR1 (NM_006767.3)c.774delT, p.(Phe258Leufs*93), hetSchwannomatosis, ADLikely pathogenic: PVS1, PM223No relevant PHx/FHx1, 2, 3
PGPC-40SLC7A9 (NM_001243036.1)c.614dupA, p.(Asn206Glufs*3), hetCystinuria, AD/ARPathogenic: PVS1, PS4-M, PP524,25No relevant PHx/FHx1, 2, 3
Mosaic Turner syndromePathogenic26No obvious clinical manifestation1, 2
PGPC-02, PGPC-27CHEK2 (NM_145862.2)c.470T > C, p.(Ile157Thr), hetCancer susceptibility, AD/ARRisk factor: PS4, PP527,2827: FHx of breast, prostate, throat cancer1, 2, 3
PGPC-25, PGPC-29F2 (NM_000506.3)c.*97G > A (20210G > A), hetThrombophilia, AD/ARRisk factor: PS3, PS42929: No relevant PHx/FHx1, 2, 3
PGPC-24LPL (NM_000237.2)c.953A > G, p.(Asn318Ser), hetDyslipidemia, AD/ARRisk factor: PS3, PS43032PHx/FHx of hypercholesterolemia, FHx of CAD (60 yr)1, 2, 3
PGPC-36MUTYH (NM_001048171.1)c.892–2A > G, p.?, hetFamilial adenomatous polyposis, AR; colorectal cancer risk, ADRisk factor (AD), pathogenic (AR): PVS1, PS3, PP5, BS133,34FHx of gastric cancer (70–80 yr)1, 2, 3
PGPC-48PCDH15 (NM_001142769.1)chr10:g. [55741501_57660800del], het (1.9 Mb)Neuropsychiatric disease risk, AD; deafness/Usher syndrome, ARRisk factor (AD), likely pathogenic (AR): PVS1, PM23538FHx of ADHD1, 3
Variants of uncertain significance
PGPC-40ANK2 (NM_001148.4)c.4373A > G, p.(Glu1458Gly), hetLong QT syndrome, cardiac arrhythmia, ADVUS: PS3, PP1, BS13941**No relevant PHx/FHx1, 2
PGPC-40CDH1 (NM_004360.3)c.2343A > T, p.(Glu781Asp), hetCDH1-related cancer, ADVUS: PM242,43FHx of gastric cancer (75–80 yr)1, 2
PGPC-19CHMP2B (NM_014043.3)c.85A > G, p.(Ile29Val), hetAmyotrophic lateral sclerosis, Frontotemporal dementia, ADVUS: PS3, PP5, BP44446No relevant PHx/FHx1
PGPC-14KCNE2 (NM_172201.1)c.29C > T, p.(Thr10Met), hetLong QT syndrome, Atrial fibrillation, ADVUS: PP5, BS147,48ND1, 2
Uncertain significance, genetic counselling recommended
PGPC-32MT-TVm.1659T > C, 7% heteroplasmyChildhood neurologic disorderLikely pathogenic††49ND1, 4
PGPC-22MultipleSeq[GRCh37] inv(20) (q11.23q13.12), chr20:g. [35583655_44214109inv], het (8.6 Mb)Likely minimal risk for unbalanced aberrations in family membersLarge, rare structural variantND1
53 of 56 PGPC participants172 recessive carrier variants (e.g., 5 pathogenic CFTR alleles)MultiplePotential disease risk in family membersRisk factorND1, 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.