InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines

Li, Quan; Wang, Kai

doi:10.1016/j.ajhg.2017.01.004

Cited by 823 publications

(671 citation statements)

References 62 publications

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“…Previous studies stated that the linker region of RAD51 paralogues is essential for protein–protein interactions,20 42 and two complexes, namely, BCDX2 and CX3, have been suggested 20 37 38. In the present study, p.Leu14Pro mutation occurred on the linker region of XRCC2 (online supplementary figure S9), and this phenomenon is different from the previously reported truncating p.Arg215*mutation that truncated a part of the C-terminal region of XRCC2 (online supplementary figure S8A) on a patient with atypical Fanconi anaemia 30 32…”

Section: Discussioncontrasting

confidence: 91%

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

et al. 2018

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BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

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Section: Discussioncontrasting

confidence: 91%

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

et al. 2018

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“…18 We found in all samples the EGFR kinaseactivating e19del mutation, and the EGFR T790M mutation responsible for gefitinib resistance (Supporting Information Table S1). 18 We found in all samples the EGFR kinaseactivating e19del mutation, and the EGFR T790M mutation responsible for gefitinib resistance (Supporting Information Table S1).…”

Section: Only Two Driver Mutations In Metastatic Lung Adenocarcinomamentioning

confidence: 89%

“…18 Mutations classified as 'likely pathogenic' or 'pathogenic' were considered. The determined polymorphisms were analysed and annotated with InterVar.…”

Section: Somatic Mutation Callingmentioning

confidence: 99%

The genomic imprint of cancer therapies helps timing the formation of metastases

Németh

Krzystanek

Reiniger

et al. 2019

Intl Journal of Cancer

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A retrospective determination of the time of metastasis formation is essential for a better understanding of the evolution of oligometastatic cancer. This study was based on the hypothesis that genomic alterations induced by cancer therapies could be used to determine the temporal order of the treatment and the formation of metastases. We analysed the whole genome sequence of a primary tumour sample and three metastatic sites derived from autopsy samples from a young never‐smoker lung adenocarcinoma patient with an activating EGFR mutation. Mutation detection methods were refined to accurately detect and distinguish clonal and subclonal mutations. In comparison to a panel of samples from untreated smoker or never‐smoker patients, we showed that the mutagenic effect of cisplatin treatment could be specifically detected from the base substitution mutations. Metastases that arose before or after chemotherapeutic treatment could be distinguished based on the allele frequency of cisplatin‐induced dinucleotide mutations. In addition, genomic rearrangements and late amplification of the EGFR gene likely induced by afatinib treatment following the acquisition of a T790M gefitinib resistance mutation provided further evidence to tie the time of metastasis formation to treatment history. The established analysis pipeline for the detection of treatment‐derived mutations allows the drawing of tumour evolutionary paths based on genomic data, showing that metastases may be seeded well before they become detectable by clinical imaging.

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“…The programmed script for the database displays the variants. The annotation was performed using relatively accepted public programs including TransVar for the coordinate conversion [18], vcfanno for the table annotation [8], Variant Effect Predictor to convert the g.HGVS format to the VCF format [16], CrossMap for the lift-over between hg10 and GRCh38 [17], and InterVar for the semi-automatic variant scoring [5].…”

Section: Methodsmentioning

confidence: 99%

Japanese pathogenic variant database: DPV

Suzuki

Kurosawa

Fukuda

et al. 2018

TRD

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Abstract. Databases of pathogenic variants form the basis for clinical genomic diagnosis using next-generation sequencers. ClinVar and the Human Gene Mutation Database (HGMD) are two major databases for pathogenic variants. However, ethnic diversity in the distributions of pathogenic variants in these databases has been observed; thus, geographic region-specific variant databases are required. We established a Japanese pathogenic variant database in 2016 and began registering pathogenic variants from published articles written by Japanese researchers. The criteria for registration are as follows: 1) the variant has been validated using Sanger sequencing, 2) the minor allele frequency of the variant is lower than 0.03 in the normal Japanese population, and 3) the clinical features of the patient have been critically evaluated by multiple clinicians and geneticists. All registered variants can be downloaded as an aggregated single VCF file to use in laboratories. We are presently curating variants from more than 2000 articles and estimate the registration of >10,000 pathogenic variants derived from the Japanese population. Although the number of registered variants remains relatively small, the clinical genetics community in Japan has begun to work on this initiative in a concerted manner.

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InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines

Cited by 823 publications

References 62 publications

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

The genomic imprint of cancer therapies helps timing the formation of metastases

Japanese pathogenic variant database: DPV

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