ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.320-5T>A (rs121908700)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212412 SCV000603086 uncertain significance not specified 2016-12-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116011 SCV000172844 likely benign Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Intronic alteration with no splicing impact by rt-pcr analysis or other splicing assay
Color RCV000116011 SCV000902592 likely benign Hereditary cancer-predisposing syndrome 2016-05-13 criteria provided, single submitter clinical testing
Counsyl RCV000195943 SCV000786412 uncertain significance Familial cancer of breast 2018-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000119289 SCV000149920 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.320-5T>A or IVS2-5T>A and consists of a T>A nucleotide substitution at the -5 position of intron 2 of the CHEK2 gene. In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. RT-PCR analysis on blood from an individual with breast and/or ovarian cancer demonstrated that this variant is associated with an aberrant in-frame transcript lacking exons 3 and 4; however the shortened transcript was present at levels less than 20% that of the wild-type transcript, leading the authors to interpret this variant as a hypomorphic allele (Kraus 2017). CHEK2 c.320-5T>A, previously published as IVS1-5T>A, was reported in other individuals with cancer, including breast cancer, colon cancer, pancreatic cancer, and lymphoma, and across studies was observed in one healthy control (Kleibl 2008, Kleibl 2009, Mohelnikova-Duchonova 2010, Havranek 2011, Havranek 2015, Tung 2015, Decker 2017). This variant was also detected in 2/708 individuals that were suspected of having hereditary breast and ovarian cancer syndrome and in a cohort of individuals with a Lynch syndrome-associated cancer and/or polyps (Castera 2014, Yurgelun 2015). CHEK2 c.320-5T>A was observed at an allele frequency of 0.4% (40/10,146) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether CHEK2 c.320-5T>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000779369 SCV000915970 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-28 criteria provided, single submitter clinical testing The CHEK2 c.320-5T>A splice region variant has been reported in a heterozygous state in at least five individuals with various cancers (Kleibl et al. 2008; Kleibl et al. 2009; Mohelnikova-Duchonova et al. 2010; Havranek et al. 2011; Kraus et al. 2016; Mucaki et al. 2016). Of these five individuals, the variant was found in one patient with sporadic breast cancer, one with colorectal cancer, one with sporadic pancreatic cancer, one with Hodgkin lymphoma, and one with hereditary breast or ovarian cancer. The c.320-5T>A variant was absent from 1366 control chromosomes (Kleibl et al. 2008), but is reported at a frequency of 0.01402 in the Iberian population in Spain from the 1000 Genomes Project. Kraus et al. (2016) demonstrated using RT-PCR analysis that the c.320-5T>A variant resulted in an in-frame transcript lacking exons 3 and 4 that was stably expressed, however at low levels (about 20%) compared to the level of wild type transcript, suggesting a leaky splicing defect and a hypomorphic allele. Based on the evidence, the c.320-5T>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000119289 SCV000154113 not provided not provided no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000119289 SCV000698794 likely benign not provided 2016-12-16 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.320-5T>A variant involves the alteration of a conserved intronic nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 63/121024 (1/1920), which exceeds the estimated maximal expected allele frequency for a pathogenic CHEK2 variant of 1/35211. Therefore, suggesting this variant is likely a benign polymorphism. Multiple publications cite the variant of interest in affected individuals, along with one publication indicating that the variant causes "leaky splicing with intron inclusion," although functional studies have not been performed to support this. Multiple clinical diagnostic laboratories have cited the variant with conflicting classifications of "likely benign" or "uncertain significance." Therefore, taking into the consideration that this variant could mildly affect splicing via in silico analyses that have yet to be functionally assessed, the variant of interest has been classified as "likely benign."
Invitae RCV000195943 SCV000253484 benign Familial cancer of breast 2018-01-12 criteria provided, single submitter clinical testing
Mendelics RCV000195943 SCV000839498 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000119289 SCV000806878 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212412 SCV000601165 uncertain significance not specified 2017-02-23 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000195943 SCV000611874 likely benign Familial cancer of breast 2018-03-28 criteria provided, single submitter research The CHEK2 variant designated as NM_007194.3:c.320-5T>A is classified as likely benign. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.38 to 1 (Thompson, et al., 2003, PMID:12900794). This likelihood ratio indicates weak evidence that the allele co-segregates disease in this family. However, RNA studies in two individuals unrelated from different families show no significant change in RNA splicing or protein transcripts, thus providing strong evidence that this variant does not alter the CHEK2 protein. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128070). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter CHEK2 function or modify cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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