chr22-28725338-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_007194.4(CHEK2):c.349A>G(p.Arg117Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 1.75
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 Pathogenic. Variant got 14 ACMG points.
PM1
In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_007194.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 22-28725338-T-C is Pathogenic according to our data. Variant chr22-28725338-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725338-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.349A>G | p.Arg117Gly | missense_variant | 3/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.349A>G | p.Arg117Gly | missense_variant | 3/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152194Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:41Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 12, 2022 | In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 31263054 (2019), 31206626 (2019), 31090900 (2019), 30303537 (2019), 30426508 (2018), 30128536 (2018), 28709830 (2017), 28503720 (2017), 27553368 (2016), 25503501 (2015)), prostate cancer (PMIDs: 29659569 (2018), 29439820 (2018)), and pancreatic cancer (PMIDs: 29945567 (2018), 29922827 (2018)). In addition, families show evidence of co-segregation with breast cancer (PMID: 12610780 (2003)). Functional studies in the published literature report this variant causes loss of CHEK2 activity (PMIDs: 30851065 (2019), 22419737 (2012), 18725978 (2008), 16982735 (2006), 16835864 (2006)). The frequency of this variant in the general population, 0.00019 (24/128958 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | CHEK2: PP1:Strong, PS4, PP3, PS3:Supporting, BP1 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2019 | Published functional studies demonstrate a damaging effect: reduced auto-phosphorylation, protein instability, impaired kinase activity, and loss of CHEK2-mediated DNA damage response (Wu 2006, Sodha 2006, Chrisanthar 2008, Roeb 2012, Delimitsou 2019); Case control study in Europeans suggests this variant is associated with female breast cancer (Southey 2016); Observed in many individuals with CHEK2-related cancers (Sodha 2002, Kleibl 2008, Desrichard 2011, Le Calvez-Kelm 2011, Roeb 2012, Castera 2014, Moran 2017, Pinto 2016, Lu 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12454775, 18058223, 22114986, 21244692, 22419737, 24549055, 27798748, 27553368, 30128536, 27595995, 16835864, 16982735, 18725978, 30851065, 33158149, 31447099, 31206626, 31263054, 30303537, 30676620, 31090900, 30322717, 29922827, 15095295, 12610780, 30666157, 30426508, 29659569, 29945567, 30067863, 30256826, 28125075, 29439820, 28553140, 28709830, 28503720, 28008555, 28452373, 27498913, 28082821, 26681312, 23555315, 27751358, 15488637, 15385111, 23960188, 15818573) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Familial cancer of breast Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 117 of the CHEK2 protein (p.Arg117Gly). This variant is present in population databases (rs28909982, gnomAD 0.02%). This missense change has been observed in individual(s) with CHEK2-related cancers (PMID: 12454775, 12610780, 21244692, 28503720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128071). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16982735, 18725878, 22419737). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PS3, PS4_STR - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 26, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
| 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]. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 27, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 22, 2017 | This CHEK2 variant was identified in a female patient diagnosed with breast cancer at 38 years old, and whose mother also have had bilateral breast cancer at ages 40 and 42 years old. Mutation screening in BRCA1 and BRCA2 genes gave negative results. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 30, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2024 | The p.R117G variant (also known as c.349A>G), located in coding exon 2 of the CHEK2 gene, results from an A to G substitution at nucleotide position 349. The arginine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in many cancer cases including familial breast/ovarian, pancreatic and colorectal and prostate cancer cohorts (Sodha N et al. Br. J. Cancer. 2002 Dec;87:1445-8; Kleibl Z et al. Breast Cancer Res. Treat. 2008 Nov;112:159-64; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Moran O et al. Breast Cancer Res. Treat. 2017 Jan;161:135-142; Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Schutte M et al. Am. J. Hum. Genet. 2003 Apr;72:1023-8). This variant has also been reported to be a possible European founder variant leading to a significant increase in prostate cancer risk (Brandão A et al. Cancers (Basel). 2020 Nov;12(11)). Multiple functional studies have found that this variant is abnormal with respect to protein stability and kinase activity (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Chrisanthar R et al. PLoS One. 2008 Aug;3:e3062; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Delimitsou A et al. Hum. Mutat. 2019 May;40(5):631-648; Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). This alteration was also more frequent in breast cancer cases than controls in a study from the Breast Cancer Association Consortium (BCAC) (Southey MC et al. J. Med. Genet., 2016 12;53:800-811). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces arginine with glycine at codon 117 in the FHA domain of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes reduced kinase activity, reduced protein stability, incomplete phosphorylation of CHEK2 protein and defective DNA damage repair (PMID: 16835864, 16982735, 18725978, 22419737, 30851065, 34903604, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 12454775, 12610780, 18058223, 21244692, 22114986, 23555315, 25503501, 27553368, 27798748, 28503720, 30128536, 31263054, 33030641, 33326660, 33803639, 35264596, 36315097), colorectal cancer (PMID: 30256826), prostate cancer (PMID: 33158149), and pancreatic cancer (PMID: 29922827, 29945567). Large case-control studies have shown that this variant is associated with an increased risk of breast cancer (OR 2.26, 95% CI [1.29 to 3.95], PMID: 27595995; OR=2.936, 95%CI [1.823 to 4.73], PMID: 33471991; OR=2.83, 95% CI [2.35 to 3.41], PMID: 37449874). This variant has been identified in 32/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been shown to cause partial loss of CHEK2 protein function and is associated with an increased risk of breast cancer. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 18, 2019 | - - |
Li-Fraumeni syndrome 2 Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2021 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Mar 06, 2023 | This variant has been identified by standard clinical testing. - |
CHEK2-related cancer predisposition Pathogenic:2Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely pathogenic and reported on 03-13-2018 by Invitae. 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 25, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18725978; 16982735; 22419737) - PS3_moderate. The c.349A>G;p.(Arg117Gly) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 128071; PMID: 12454775; PMID: 12610780; PMID: 21244692; PMID: 28503720) -PS4. The variant is present at low allele frequencies population databases (rs28909982 – gnomAD 0.001132%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 15, 2018 | The CHEK2 c.349A>G p.(Arg117Gly), also referred to c.478A>G (Arg160Gly), missense variant has been identified in individuals with a phenotype consistent with CHEK2-related cancer susceptibility. In two individuals, other pathogenic BRCA2 and CHEK2 variants were also identified (Sodha et al. 2002; Schutte et al. 2003; Le Calvez-Kelm et al. 2011; Southey et al. 2016; Susswein et al. 2016). In a large case-control study, Southey et al. (2016) showed that the p.(Arg117Gly) variant was significantly associated with breast cancer in European women (odds ratio of 2.26). In this study, odd ratios were not statistically significant for prostate cancer or ovarian cancer. The variant segregated with breast cancer in one family whereas in two families incomplete segregation was observed whereby two affected individuals did not carry the variant (Schutte et al. 2003). The highest frequency of this allele in the Genome Aggregation Database is 0.000186 in the European (non-Finnish) population (version 2.1.1). Functional studies in cells lines demonstrated reduced protein expression and stability, and impaired phosphorylation and kinase activity of the variant protein when compared to wildtype protein. However, the variant protein dimerized efficiently to wildtype CHEK2 (Sodha et al. 2006; Wu et al. 2006; Chrisanthar et al. 2008). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.349A>G p.(Arg117Gly) variant is classified as likely pathogenic for CHEK2-related breast cancer susceptibility. - |
CHEK2-related disorder Pathogenic:2
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 04, 2024 | The CHEK2 c.349A>G variant is predicted to result in the amino acid substitution p.Arg117Gly. This is a well-documented variant reported in multiple individuals with cancers of breasts, colon, skin, kidneys, thyroid, ovaries and prostate gland (Table S1, Susswein et al. 2016. PubMed ID: 26681312; Southey et al. 2016. PubMed ID: 27595995). Earlier, Schutte and colleagues had described this variant as having no major contribution to susceptibility to breast cancer (Schutte et al. 2003. PubMed ID: 12610780). However, more recently the authors reported it to be associated with increased risk for breast cancer, but not for prostate and ovarian cancers (Southey et al. 2016. PubMed ID: 27595995). Several functional studies on this variant have indicated impaired CHEK2 functions, specifically the kinase activity and DNA damage response (Chrisanthar et al. 2008. PubMed ID: 18725978; Roeb et al. 2012. PubMed ID: 22419737). The Arg117 residue, located within the forkhead-associated domain of the CHEK2 protein, has been highly conserved during evolution (http://www.uniprot.org/uniprot/O96017). This variant is listed in the ClinVar database with interpretations of likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128071/). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 03, 2022 | PS3, PS4, PP3 - |
Malignant tumor of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2022 | Variant summary: CHEK2 c.349A>G (p.Arg117Gly) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant allele was found in 33/265114 control chromosomes at a frequency of 0.00012 (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00012 vs 0.00031), allowing no conclusion about variant significance. The variant, c.349A>G, has been reported in the literature in multiple individuals affected with cancer including breast cancer, pancreatic cancer, colorectal cancer and prostate cancer (but also in controls) (Hu_2018, Lu_2018, Martin-Morales_2018, Paulo_2018, Rummel_2017, Pinto_2016, Southey_2016), with limited cosegregation information. In one study, in 3 families, 8 transmissions of the variant allele and 2 transmissions of the reference allele to affected individuals was reported (Schutte_2003). The variant has also been reported in studies that included cohorts of comprehensively genotyped patients with early onset breast cancer meeting the NCCN guidelines (Rummel_2017), and a family history of breast cancer (Pinto_2016; Moran_2017, Lu_2018). A case-control study showed evidence of association with breast cancer (OR = 2.03; Southey_2016) but no association with prostate and ovarian cancer, suggesting this might be a risk variant. FLOSSIES database reports the variant in 2 women older than age 70 years who have never had cancer. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.891_899delAACAGTTGTinsGATACTTCAG, p.Thr298Ilefs; CHEK2 c.1100delC, p.Thr367fsX15 (Susswein_2015); APC c.426_427delAT, p.Leu143AlafsX4 at our laboratory). However, as co-occurrence with other pathogenic variants is not mutually exclusive in cancer probands, this is not entirely supportive of a benign role of this variant. Functional in vitro and in vivo studies showed that p.R117G is incompletely phosphorylated and is not efficiently activated in response to DNA damage, showing minimal kinase activity when studied in isolation, however, it can dimerize efficiently to CHEK2 wild-type without strongly affecting the wild-type CHEK2 activity (Roeb_2012, Chrisanthar_2008, Sodha_2006, Wu_2006). Twenty ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (n=16) and pathogenic (n=4). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg117Gly variant was identified in 55 of 88752 proband chromosomes (frequency: 0.0006) from individuals or families with hereditary breast and ovarian cancer (Desrichard 2011, Kleibl 2008, Moran 2017, Pinto 2016, Schutte 2003, Sodha 2002, Southey 2016, Wu 2006). The variant was also identified in dbSNP (ID: rs28909982) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx and Mayo Clinic; and as likely pathogenic by Ambry Genetics, Invitae, Color Genomics, University Hospital of Geneva, and Counsyl), MutDB, and Zhejiang Colon Cancer Database (4x). The variant was not identified in the Cosmic database. The variant was identified in control databases in 31 of 276970 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24030 chromosomes (freq: 0.00008), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 4 of 34418 chromosomes (freq: 0.0001), European in 22 of 126468 chromosomes (freq: 0.0002), Finnish in 2 of 25792 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg117Gly variant has been extensively studied in the literature. In vitro studies have demonstrated that the Arg117Gly variant has strongly reduced kinase activity (Chrisanthar 2008). Multiple studies found that following DNA damage with ionizing radiation, the variant protein demonstrated greatly reduced CHEK2 kinase activity (Wu 2006, Roeb 2012, Le Calvez-Kelm 2011). In addition, studies have shown that the protein encoded by this allele is phosphorylated by ATM in response to DNA damage, shows slightly to markedly reduced autophosphorylation, probably fails to oligomerize, and has severely compromised kinase activity. Sodha (2006) also concluded through bioinformatic analysis that the variant is likely to be deleterious and functional studies showed that the variant protein is less stable than the wild type protein. The p.Arg117Gly residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 18, 2023 | - - |
Breast cancer, susceptibility to;C3469524:Prostate cancer susceptibility Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2018 | The c.349A>G(p.Arg117Gly) variant in the CHEK2 gene (seen 31 times in gnomAD) has been observed in multiple unrelated probands and segregated in one family with BRCA1/2 negative breast cancer (PMID 12454775, 12610780, 18058223, 27595995, 27553368, 27798748). Although not validated for clinical use, the in silico programs predict this variant to be damaging. Experimental studies are consistent with this variant resulting in disruption of CHEK2 function (PMID 16982735, 16835864, 22419737). Therefore, this c.349A>G (p.Arg117Gly) variant in the CHEK2 gene is classified as pathogenic. - |
Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 08, 2021 | - - |
Predisposition to cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | May 13, 2021 | The CHEK2 c.349A>G (p.Arg117Gly) missense change has a maximum frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/22-29121326-T-C?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). Several functional studies suggest that this variant is pathogenic, demonstrating a strongly reduced CHEK2-mediated DNA damage response, impaired kinase activity, and incomplete phosphorylation (PS3; PMID: 18725978, 22419737, 30851065, 16835864, 16982735). This variant has been identified in many cancer cases including familial breast/ovarian, prostate, pancreatic, colorectal, as well as other cancer types (PMID: 12454775, 15095295, 21244692, 26681312, 28125075, 29439820, 29659569, 29439820, 29945567, 30322717, 30256826, 28709830, 30426508, 31090900, 31263054, 31206626, 32906215, 30676620, 32906215). A case-control study showed evidence of association with breast cancer (PS4; OR = 2.26; PMID: 27595995), but no association with prostate and ovarian cancer. In addition, the variant segregated with breast cancer in three families, although it was not identified in all affected family members (PMID: 12610780) This variant is present 2x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PS3, PS4, PP3, BS2_supporting. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Molecular Oncology Research Center, Barretos Cancer Hospital | Aug 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;D;.;D;.;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;.;H;H;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D;D;D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;.;D;D;D;.;.;.
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;.;.
Polyphen
D;D;D;D;D;D;D;.;.;.;.;.
Vest4
MVP
MPC
0.17
ClinPred
D
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