Table 4.
List of variants in known high-risk genes in breast, colorectal, and prostate cancers found in cancer-free families (CFFs) with annotations. For the ExAc population, probability of carrying a pathogenic/likely pathogenic variant is shown.
| Gene | Missense + LoF Variants in ExAC | Missense + LoF Variants in CFF | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total No. | No. Pathogenic | p ExAC 1 | SNP ID | Chr | Position | Ref/Alt | Prevalence ExAC NFE |
CADD | Positive Conservation Scores | Positive Prediction Tools | ClinVar Significance | |
| BRCA2 | 691 | 40 | 0.112% | rs397507270 | 13 | 32907128 | A/G | 1.51 × 10−5 | 0.11 | 0 | 1 | Likely benign/US |
| rs56087561 | 13 | 32913562 | A/C | 3.65 × 10−4 | 24.1 | 2 | 5 | Benign | ||||
| rs80358768 | 13 | 32913947 | C/T | 3.45 × 10−4 | 0.2 | 0 | 1 | Benign | ||||
| APC | 481 | 2 | 0.003% | rs748940586 | 5 | 112178309 | A/C | 1.51 × 10−5 | 22.7 | 3 | 8 | US |
| No dbSNP | 5 | 112178460 | GTAT/G | . | 21.8 | . | . | - | ||||
| MLH1 | 167 | 3 | 0.008% | rs41294980 | 3 | 37067306 | G/A | 1.18 × 10−3 | 7.3 | 1 | 0/4 2 | Benign |
| rs63751225 | 3 | 37090075 | T/C | 1.80 × 10−4 | 22.1 | 3 | 4 | US | ||||
| MSH2 | 246 | 4 | 0.006% | rs116117580 | 2 | 47739533 | G/A | 1.99 × 10−2 | 0.003 | 0 | 1 | Not provided |
| MSH6 | 359 | 8 | 0.017% | rs752887988 | 2 | 48010377 | C/T | 0 | 33 | 3 | 7 | - |
| rs267608075 | 2 | 48028282 | A/T | 1.83 × 10−4 | 13.0 | 3 | 5 | Benign/US | ||||
| MUTYH | 174 | 12 | 0.079% | rs36053993 | 1 | 45797228 | C/T | 3.96 × 10−3 | 29.4 | 3 | 3/4 2 | Likely Pathogenic/Pathogenic |
| PMS2 3 | 172 | 12 | 0.021% | No dbSNP | 7 | 6043400 | T/C | . | 24.9 | 3 | 6 | - |
| BRCA1 | 344 | 17 | 0.071% | Not found | - | - | - | - | - | - | - | - |
| HOXB13 3 | 62 | 0 | Not found | - | - | - | - | - | - | - | - | |
LoF: loss-of-function, stop gain/loss, splice-site, and frameshift indel variants; No: number; NFE: Non-Finnish European; US: uncertain significance; Conservational Scores: Genomic Evolutionary Rate Profiling (GERP), PhastCons, and Phylogenetic P-value (PhyloP); inclusion cutoff ≥ 2/3; Prediction Tools: Sorting Intolerant from Tolerant (SIFT), Polymorphism Phenotyping version-2 (PolyPhen-2) HDIV (HumDiv), PolyPhen-v2 HVAR (HumVar), Log ratio test (LRT), MutationTaster, Mutation Assessor, Functional Analysis Through Hidden Markov Models (FATHMM), MetaSVM, MetaLR, Protein Variation Effect Analyzer (PROVEAN); inclusion cutoff ≥ 6/10; 1 probability of carrying pathogenic/likely pathogenic non-synonymous and loss of function (LoF) variants in the ExAC population; 2 data from 4 prediction tools available; 3 the high-risk status of PMS2 and HOXB13 is under discussion.