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
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.
Ambry Genetics RCV000116011 SCV000172844 likely benign Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing 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
Invitae RCV000119289 SCV000253484 benign not provided 2019-03-05 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212412 SCV000603086 uncertain significance not specified 2016-12-25 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 analyze.myvariant.org (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.
Integrated Genetics/Laboratory Corporation of America RCV000212412 SCV000698794 benign not specified 2019-04-11 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.320-5T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict the variant slightly weakens a 3 acceptor site. An in silico analysis also predicted the variant to result in a reduced splicing efficiency that could activate pre-existing cryptic acceptor 92 nucleotide upstream of the natural site, leading to the inclusion of 92 nucleotide of the intron. However this effect was predicted to be partial, with the variant mRNA relatively less abundant compared to the wild type (Mucaki 2016). Two publications reported experimental evidence evaluating splicing impact: one identified an in frame transcript variant lacking exon 3 and 4, however, the amount of the shortened transcript compared to wild type was less than 20%, suggesting that this variant reduces but does not eliminate the usage of the consensus splice acceptor and can therefore be regarded as a hypomorphic allele (Kraus 2017); whereas the other study reported splice analysis from 2 patients showing no significant change in RNA splicing, however without providing experimental evidence (Tsai 2018). The variant allele was found at a frequency of 0.00053 in 288862 control chromosomes (gnomAD and publication data), including 1 homozygote. The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is benign. In addition, this variant has been reported in 10/9884 American women who are older than age 70 and cancer free (FLOSSIES database). c.320-5T>A has been reported in the literature in individuals affected with various tumor phenotypes, including breast-/ovarian-, colorectal- and pancreas cancer, non-Hodgkin lymphoma and Lynch syndrome (Kleibl 2008, Kleibl 2009, Mohelnikova-Duchonova 2010, Havranek 2015, Castera 2014, Tung 2015, Yurgelun 2015, Kraus 2017, Decker 2017, Bonache 2018, Hampel 2018). These reports however do not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, in two of these patients co-occurrences with other pathogenic variants have been reported (CHEK2 exon 2 deletion, Tung 2015; MLH1 c.1381A>T/K461X, Hampel 2018), providing supporting evidence for a benign role. Though one case-control study suggested that the variant might be associated with breast cancer, the carrier frequency in healthy controls recruited in this study was much lower than observed in population datasets, therefore this postulation might be the result of sampling error (Decker 2017). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (6 calling it a VUS, 2 classifying as likely benign, and 1 as benign). Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000195943 SCV000786412 uncertain significance Familial cancer of breast 2018-04-26 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000119289 SCV000806878 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing
Mendelics RCV000195943 SCV000839498 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000116011 SCV000902592 likely benign Hereditary cancer-predisposing syndrome 2016-05-13 criteria provided, single submitter clinical testing
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

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