22-28734532-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_007194.4(CHEK2):c.190G>A(p.Glu64Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
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5
13
Clinical Significance
Conservation
PhyloP100: 3.49
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.13926247).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.190G>A | p.Glu64Lys | missense_variant | 2/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.190G>A | p.Glu64Lys | missense_variant | 2/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.000145 AC: 22AN: 151916Hom.: 0 Cov.: 31
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:16Uncertain:19Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:7Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | CHEK2: PS4, PS3:Moderate, BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 28, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 16, 2024 | The CHEK2 c.190G>A (p.Glu64Lys) variant has been reported in the published literature in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), breast cancer and/or ovarian cancer (PMID: 22419737 (2012), 25186627 (2015), 26976419 (2016), 26681312 (2016), 26845104 (2016), 27616075 (2016), 27779110 (2017), 28779002 (2017), 29555771 (2018), 30322717 (2018), 30303537 (2019), 31050813 (2019), 32923877 (2020), 31786208 (2020), 32805687 (2020), 33919281 (2021), 33471991 (2021)) and colorectal cancer (PMID: 28135145 (2017)). The variant has also been reported in at least one reportedly healthy individual (PMID: 26506619 (2015), 28779002 (2017), 30303537 (2019), 33471991 (2021)). Functional studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function (PMID: 16835864 (2006), 22419737 (2012), 30851065 (2019), 37449874 (2023)). The frequency of this variant in the general population, 0.00031 (16/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2024 | BP4 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2024 | Observed in individuals with CHEK2-related cancers with case-control comparisons supporting this variant is associated with breast cancer (PMID: 22419737, 34326862, 34903604, 37449874, 37839337); Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID: 16835864, 22419737, 30851065, 31050813, 34903604, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 27616075, 28135145, 29522266, 27779110, 27433846, 31786208, 33919281, 35053600, 32906215, 22419737, 16835864, 24082139, 16941491, 22114986, 12533788, 27067391, 26976419, 26506619, 26845104, 27696107, 28135136, 27621404, 28726808, 28873162, 29555771, 29555025, 10973490, 30851065, 31050813, 31220302, 30322717, 31159747, 30303537, 30374176, 31101557, 32805687, 31980526, 32708810, 34426522, 34903604, 33606978, 32522261, 32923877, 35101071, 33047316, 33471991, 38061684, 34326862, 37449874, 36011273, 36315097, 35127508, 37507557, 37839337, 11733767) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 28, 2022 | The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, Toss 2021). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068) and is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.240). Given the currently available information, the clinical significance of this variant is uncertain at this time. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. PMID: 12533788. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Toss A et al. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021 Apr 21;12(5):616. PMID: 33919281. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7. PMID: 16835864. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Familial cancer of breast Pathogenic:4Uncertain:3Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 14, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Mar 27, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 15, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein (p.Glu64Lys). This variant is present in population databases (rs141568342, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 12533788, 22114986, 24082139, 26681312, 26845104, 27616075, 27779110, 28135145; Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 11, 2023 | Criteria applied: PS3,PS4_MOD - |
Hereditary cancer-predisposing syndrome Pathogenic:4Uncertain:3
| Likely pathogenic, no assertion criteria provided | clinical testing | True Health Diagnostics | Mar 16, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Aug 04, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 12, 2023 | This missense variant replaces glutamic acid with lysine at codon 64 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604). One study has shown normal growth of yeast cells expressing the mutant protein following induction of DNA damage (PMID, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501, 26681312, 26845104, 26976419, 27616075, 31050813, 33919281, 36011273, 36315097), colorectal cancer (PMID: 26681312, 27696107, 28135145), ovarian cancer (PMID: 26681312, 27779110), pancreatic cancer (PMID: 26845104), prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), and sarcoma (PMID: 35053600). In one study, breast cancer prevalence in women who carry this variant does not show statistically significant difference when compared to women who carry CHEK2 c.1100delC variant (PMID: 32805687). However, this variant has also been reported in two large breast cancer case-control meta-analyses, in 66/60466 cases and 33/53461 unaffected controls; OR=1.769 (95%CI 1.165 to 2.687); (Leiden Open Variation Database DB-ID CHEK2_000075) (PMID: 33471991), and 72/73048 cases and 29/88658 unaffected controls OR=3.0153 (95%CI 1.9592 to 4.6408); (PMID: 37449874). This variant has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, its elevated frequency in the population and observations in unaffected individuals suggests that this variant may show reduced penetrance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2024 | The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies conducted in multiple model systems have conflicting results as to the effect this protein has on substrate phosphorylation and DNA damage response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer. 2019 10;145:1782-1797; Boonen RACM et al. Cancer Res. 2022 Feb;82(4):615-631; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Although this variant may segregate incompletely with disease, co-segregation analysis should be used with extreme caution for genes with low relative risk like CHEK2 (Belman S et al. Genet. Med. 2020 Dec;22:2052-2059). This amino acid position is poorly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Cancer Genomics Lab, PINUM Cancer Hospital | May 18, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 19, 2021 | - - |
Li-Fraumeni syndrome 2 Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Roeb, et al 2012).This variant has been reported to the ClinVar database as Uncertain Significance.The p.Glu64Lys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0001591 is reported in gnomAD. The amino acid Glu at position 64 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu64Lys in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 11, 2024 | Criteria applied: PS3,PS4_MOD - |
Breast and/or ovarian cancer Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 30, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | case-control;clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
CHEK2-related cancer predisposition Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Likely pathogenic, no assertion criteria provided | research | University of Washington Department of Laboratory Medicine, University of Washington | Sep 09, 2019 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | May 03, 2024 | Neueste funkt. Daten von Stolarova et al. 2023 neutral in CHK2 assay intermediate in KAP1 Assay. Roeb 2012 kommt hier auf ein ´´damaging´´; Kleiblova 2019 auf ein ´´deleterious´´, Boonen 2021 kommt auf ein ´´intermediate´´ während Delimitosu 2019 die Veränderung als benign einstuft. Boonen et al diskutieren sehr schön die diskordanten Ergebnisse in Hefe und Mensch und zeigen noch ein weiteres Problem der Hefeassays auf, nämlich die Analyse bei 30 Grad statt 37 Grad, was natürlich Auswirkungen auf Proteinstabilitäten hat. Wu X, Dong X, Liu W, et al.: Characterization of CHEK2 mutations in prostate cancer. Hum Mutat 2006;27:742–7 ´´reduced autophosphorylation, CDC25C phosphorylation and severely impaired T68 phosphorylation´´. In der Arbeit von Dorling et al. (BRIDGES/BCAC) wurde die Variante 60X in 60.000 BC cases und 30X in 53.000 Kontrollen gefunden. Vgl. c.1100delC 868X in 60.000 cases und 254X in 53.000 Kontrollen.Evtl. handelt es sich um eine hypomorphe Variante - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2023 | Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251468 control chromosomes, predominantly at a frequency of 0.0003 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (0.00031), suggesting that it could be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously, allowing no conclusion about variant significance.c.190G>A has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (examples: Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Carter_2018, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, and Dorling 2021) without evidence for causality, but also in controls (examples: Girard_2019, Kleiblova_2019, and Dorling 2021). However, in at least one family study, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals were reported, thus the variant did not co-segregate with disease (Kleiblova_2019). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The variant has also been reported in individuals with other cancer phenotypes, including colorectal cancer (examples- Susswein_2015, Rohlin_2016, Yurgelun_2017), prostate cancer (examples-Dong_2003, Wu_2006, Pritchard_2016, Abida_2017), and hereditary pancreatic cancer (example- Chaffee_2018). Several publications report experimental evidence evaluating an impact on protein function. Assays performed in yeast model systems have reported conflicting results: one study found that the variant impaired growth following DNA damage (Roeb_2012), while a similar study reported no significant impact on growth (Delimitsou_2019). Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 12533788, 26681312, 16835864, 26845104, 22114986, 27621404, 27616075, 27433846, 27696107, 28135145, 28726808, 30851065, 30374176, 30447919, 30322717, 30303537, 31159747, 31398194, 31050813, 28825054, 31786208, 31980526, 32906215, 33471991, 32923877, 33919281, 34903604). Twenty-three ClinVar submitters have assessed the variant since 2014: fourteen classified the variant as uncertain significance and 9 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
CHEK2-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or family history of prostate, breast, ovarian, and colon cancer (Dong et al. 2003. PubMed ID: 12533788; Table S7, Gonzalez-Garay et al. 2013. PubMed ID: 24082139; Table1, Wu et al. 2006. PubMed ID: 16835864; Desrichard et al. 2011. PubMed ID: 22114986; Table S1, Susswein et al. 2015. PubMed ID: 26681312; Supp. Table 4, Kraus et al. 2016. PubMed ID: 27616075; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864). However, studies using a yeast functional assay to assess DNA damage response suggests this variant may be benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). An internal summary of amino acid substitution prediction programs gives conflicting predictions for the p.Glu64Lys change (Liu et al. 2016. PMID: 26555599). This variant has been observed in up to 0.03% of individuals of European (non-Finnish) descent in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128068/). Based on the current available evidence we classify this variant as likely pathogenic. - |
Predisposition to cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 03, 2022 | The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be associated with cancer susceptibility (PMID: 12533788, 16835864, 16941491, 22114986, 24082139, 25503501, 26681312, 26845104, 26976419, 27433846, 27616075, 27696107, 27779110, 28135145, 31050813, 31220302). In a large breast cancer case-control analysis, the variant was enriched in breast cancer cases compared to controls (PMID: 33471991). It has also been reported in 11x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (http://whi.color.com). Large co-segregation studies have not been performed, however co-segregation in families is variable and the p.E64K has been observed in at least one individual who also harbored the p.I157T (PMID: 30374176, 31050813). Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813), however yeast-based DNA damage repair assays are inconclusive about a pathogenic or benign effect (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic with evidence suggesting lower penetrance. - |
Breast and colorectal cancer, susceptibility to Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Sep 09, 2019 | This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL
Benign
Sift
Benign
T;T;T;T;D;.;D;T;T;D;D;.;.
Sift4G
Benign
T;T;T;T;D;.;D;T;D;D;D;.;.
Polyphen
B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4
MVP
MPC
0.021
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at