Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

Dorschner, Michael O.; Amendola, Laura M.; Turner, Emily H.; Robertson, Peggy D.; Shirts, Brian H.; Gallego, Carlos J.; Bennett, Robin L.; Jones, Kelly L.; Tokita, Mari; Bennett, James T.; Kim, Jerry H.; Rosenthal, Elisabeth; Kim, Daniel S.; Tabor, Holly K.; Bamshad, Michael J.; Motulsky, Arno G.; Scott, C. Ronald; Pritchard, Colin C.; Walsh, Tom; Burke, Wylie; Raskind, Wendy H.; Byers, Peter H.; Hisama, Fuki M.; Nickerson, Deborah A.; Jarvik, Gail P.

doi:10.1016/j.ajhg.2013.08.006

Cited by 354 publications

(351 citation statements)

References 27 publications

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“…6 A major opportunity for clinical genetics lies in ''actionable'' genes (e.g., BRCA1 [MIM: 113705] and breast cancer [MIM: 604370]), where knowledge of a pathogenic variant provides the evidence for changes in medical management. 7 Except for obviously pathogenic nonsense and canonical splicesite variants, newly observed variants in actionable genes do not usually have enough evidence to be classified as either pathogenic or benign and are therefore interpreted as VUSs. A VUS can be confusing for patients and physicians because it creates uncertainty and cannot be used for guiding diagnosis or management.…”

Section: Introductionmentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

316

294

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Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of ''lookup tables'' of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

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Section: Introductionmentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

316

294

View full text Add to dashboard Cite

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“…Since the ACMG released their recommendations, several groups have tried to estimate frequencies of actionable variants in 56 genes for diverse samples and by using different methods [10][11][12][13][14][15]. Using WGS or WES data, some studies [15,16] tried to estimate the frequencies of pathogenic variants in the recommended genes for European and African ancestries, and target populations of the 1000 Genomes Project.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

et al. 2017

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

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“…The GG allele was the most frequent similar to European Caucasian population [29]. A characteristic insertion (T>TA) in exon 18 was also found in most of patients (homozygous TA/TA in patients IDs 1,2,4,7,8,9,10,11,13,14,15,16,17,22,23 and 24), (heterozygous T>TA, rs3830355, IVS18-50insA in patients IDs 3, 5,6, 12 and 18). Both PDGFRA exon 18 mutation and exon 12 mutation were related more to gastric and intestinal GIST (gastrointestinal tumors) more than to colonic [30].…”

Section: Missense Splicing and Indels Mutationsmentioning

confidence: 61%

“…C>T, rs28934575, Gly245Ser which was previously described in CRC [20] and G>A, rs121912651, Arg248Trp which is a well-known pathogenic variant in CRC [21]. Exon 8 has got 2 pathogenic variants that are associated with Li-Fraumeni syndrome (G>A, rs149633775-Arg283Cys, C>T and rs763098116-Cys277Phe) [22]. Generally, TP53 has got 29 missense mutations; 7 were reported as pathogenic, 3 with uncertain significance and the remaining missense mutations were benign/ likely benign.…”

Section: Pathogenic and Likely Pathogenic Variants In The Crc Cohortmentioning

confidence: 99%

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

Farghal¹,

Saied²,

Ghaith³

et al. 2017

J Cancer Sci Ther

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Background: Colorectal carcinoma (CRC) is a burden problem in a developing country like Egypt since patients are usually admitted in late stage with bad prognosis and short overall survival. Because of genetic predisposition of CRC and introduction of advanced molecular techniques, efforts are directed to screen for potential pathogenic or disease-causing variants in CRC patients Methods: DNA was isolated from formalin fixed paraffin embedded tissue sections collected from 24 CRC confirmed diagnosed patients. TruSight CRC panel (Illumina) was used for detection of different variants in 15 genes. The generated reads were obtained from Illumina Miseq were clustered into single nucleotide polymorphism (SNPs) and small insertions/deletions (Indels). Further pathogenic variants with somatic and germline mutations were identified according to the recommended criteria. Some CRC patients were subjected to anti-EGFR target therapy.Results: Most of the variants were detected in TP53 gene 140 variants (65%); 105 short deletions none of them was pathogenic, 29 missense mutations and 6 SNPs at splicing sites. Next, ERBB2 has got 17 variants (8.8%) (missense and splicing), 8 of them were damaging disease causing variants. Besides, 16 pathogenic variants were identified in 12 patients (6 in TP53 and 7 in KRAS). Some pathogenic variants were not reported before in CRC e.g. TP53 C>A, rs121912654, Val157Phe. Additionally, patients carried different KRAS wild mutations showed variable response to anti-EGFR target therapy. Conclusion:The most affected pathway in CRC was TP53 pathway followed by ERBB2, NRAS, KRAS and PIK3CA genes. Variable response to target therapy suggested dependence on the type of pathogenic variant identified, also a possible role of ERBB2 which had a significant variant frequency.NRAS. The prevalence rate of TP53 mutation in Arab population is 52.5% compared to 47.5% in matched Western population [7]. TP53 mutations have roles in determining progression, invasiveness and also metastasis of CRC. So, CRC patients with mutant TP53 have more progressive phenotype and poorer survival than those with TP53 wild type [8]. The phosphatidylinositol 3-kinase/Akt/mammalian target of

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Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

Cited by 354 publications

References 27 publications

Variant Interpretation: Functional Assays to the Rescue

Variant Interpretation: Functional Assays to the Rescue

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

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