chr22-28734532-C-T
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting
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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E64V) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
Publications
- CHEK2-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
- Li-Fraumeni syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- acute myeloid leukemiaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | MANE Select | c.190G>A | p.Glu64Lys | missense | Exon 2 of 15 | NP_009125.1 | ||
| CHEK2 | NM_001005735.3 | c.190G>A | p.Glu64Lys | missense | Exon 2 of 16 | NP_001005735.1 | |||
| CHEK2 | NM_001438293.1 | c.190G>A | p.Glu64Lys | missense | Exon 2 of 16 | NP_001425222.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | TSL:1 MANE Select | c.190G>A | p.Glu64Lys | missense | Exon 2 of 15 | ENSP00000385747.1 | ||
| CHEK2 | ENST00000382580.6 | TSL:1 | c.190G>A | p.Glu64Lys | missense | Exon 2 of 16 | ENSP00000372023.2 | ||
| CHEK2 | ENST00000402731.6 | TSL:1 | c.190G>A | p.Glu64Lys | missense | Exon 1 of 13 | ENSP00000384835.2 |
Frequencies
GnomAD3 genomes 0.000145 AC: 22AN: 151916Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000155 AC: 39AN: 251468 AF XY: 0.000140 show subpopulations
GnomAD4 exome AF: 0.000171 AC: 250AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.000153 AC XY: 111AN XY: 727240 show subpopulations
Age Distribution
GnomAD4 genome 0.000145 AC: 22AN: 151916Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74182 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:7Other:1
BP4
DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.190G>A, in exon 2 that results in an amino acid change, p.Glu64Lys. The p.Glu64Lys change affects a poorly conserved amino acid residue located in a domain of the CHEK2 protein that is not known to be functional. The p.Glu64Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in other individuals with prostate cancer, breast cancer, ovarian cancer, colorectal cancer and pancreatic cancer and has been found to segregate with disease in some families (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302, 22114986, 25503501, 26976419, 27616075, 31050813, 26681312,27696107, 28135145, 26681312, 27779110, 26681312, 26845104, 31050813). This sequence change has been described in the gnomAD database with a frequency of 0.030% in the European subpopulation (dbSNP rs141568342). This variant has also been identified in 11 of 9884 females over the age of 70 without personal history of cancer (FLOSSIES database). Functional cell based assay showed reduction in phosphorylation and kinase activity (PMID: 16835864, 31050813) but yeast based assays had conflicting results in DNA damage repair assays (PMID 22419737, 30851065). These collective evidences indicate that this sequence change is likely pathogenic however additional studies are required to prove this conclusively. While the penetrance of this variant has not been determined, the elevated frequency in population databases and population matched controls (gnomAD, FLOSSIES) suggests that this variant may have decreased penetrance.
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.
CHEK2: PS4, PS3:Moderate, BS2
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)
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.
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.
Familial cancer of breast Pathogenic:4Uncertain:4Other:1
Criteria applied: PS3,PS4_MOD
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; External communication, internal data). 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.
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.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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].
Hereditary cancer-predisposing syndrome Pathogenic:4Uncertain:4
ClinVar LP/VUS
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 individuals diagnosed with breast, ovarian and prostate cancer (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. The in silico prediction by BayesDel for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
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. 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.
CHEK2-related cancer predisposition Pathogenic:2Uncertain:3
The variant CHEK2: c.190G>A p.(Glu64Lys), located in the coding exon 2 of CHEK2 gene, results from a guanine to adenine substitution at nucleotide position c.190. The glutamine residue at protein position 64 is replaced by a lysine. In silico tools predict no deleterious effect in the protein structure/function (REVEL = 0,24). The variant has conflicting classification for pathogenicity in ClinVar (ClinVar ID: 128068) with twelve entries for Likely Pathogenic and 19 for variant of uncertain significance. This variant is classified as rare in the overall population (MAF 1,6 * e-4 in gnomAD, v4.1.0). In summary, the variant is classified as variant of uncertain significance.
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.
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.
Criteria applied: PS3,PS4_MOD
Hereditary breast ovarian cancer syndrome Pathogenic:1Uncertain:2
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
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. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00016 vs 0.00031), allowing no conclusion about variant significance. c.190G>A has been reported in the literature in individuals affected with breast or ovarian cancer (e.g. Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, Dorling 2021, Infante_2024), and in those affected with other cancer types related to Hereditary Breast And Ovarian Cancer Syndrome, such as prostate, colorectal, and pancreatic cancers (e.g. Rohlin_2016, Wu_2006, Pritchard_2016, Yurgelun_2017, Dong_2003, Orsi_2024, Abida_2017, Chaffee_2018). However, the variant has also been reported in controls (e.g. Girard_2019, Kleiblova_2019, and Dorling 2021), and in at least one family study, the variant was not transmitted to an affected individual from an affected parent, thus the variant did not segregate with disease (Kleiblova_2019). 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). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28825054, 31398194, 39029294, 34903604, 38061684, 28726808, 30851065, 22114986, 12533788, 33471991, 30303537, 32923877, 31980526, 31050813, 27616075, 27433846, 31786208, 22419737, 27696107, 26845104, 26681312, 33919281, 30374176, 31159747, 32906215, 16835864, 28135145, 30447919). ClinVar contains an entry for this variant (Variation ID: 128068). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PM2_Suporting+PP3+BP1
Breast and/or ovarian cancer Pathogenic:1Uncertain:1
CHEK2-related disorder Pathogenic:1
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.
Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition Pathogenic:1
Breast and colorectal cancer, susceptibility to Pathogenic:1
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.
Predisposition to cancer Pathogenic:1
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.
not specified Uncertain:1
Malignant tumor of breast Uncertain:1
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.
Neoplasm Other:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at