ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.349A>G (p.Arg117Gly) (rs28909982)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212414 SCV000149921 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.349A>G at the cDNA level and p.Arg117Gly (R117G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has been reported in several individuals with familial breast cancer (Sodha 2002, Kleibl 2008, Desrichard 2011, Le Calvez-Kelm 2011, Roeb 2012, Castera 2014, Moran 2016, Pinto 2016). The variant segregated with disease in three small families, present in most, but not all, cases of breast cancer (Schutte 2003). In addition, multiple functional studies suggest this variant is pathogenic, demonstrating loss of CHEK2-mediated DNA damage response, protein instability, reduced phosphorylation, and impaired kinase activity (Wu 2006, Sodha 2006, Chrisanthar 2008, Roeb 2012). Finally, in a large meta-analysis, this variant was shown to be significantly associated with breast cancer in European women, with an odds ratio of 2.26 (p=0.003) (Southey 2016). CHEK2 Arg117Gly was observed at an allele frequency of 0.02% (22/126,468) in individuals of European ancestry in large population cohorts (Lek 2016). CHEK2 Arg117Gly is located in the forkhead-associated (FHA) domain (Cai 2009, Roeb 2012). In silico analysis, including protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this to be a pathogenic variant.
Ambry Genetics RCV000116012 SCV000183898 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing 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). 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). 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.
Invitae RCV000204429 SCV000262374 likely pathogenic Familial cancer of breast 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 117 of the CHEK2 protein (p.Arg117Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs28909982, 0.02%). This variant has been observed in families affected with breast and other cancers (PMID: 12454775, 12610780, 21244692, 28503720). It has been shown to co-segregate with disease in several affected families, but the segregation was considered incomplete because two affected individuals did not carry this variant (PMID: 12610780). ClinVar contains an entry for this variant (Variation ID: 128071). Experimental studies have shown that this variant results in a CHEK2 protein with impaired function due to reduced kinase activity, reduced protein stability, and incomplete phosphorylation (PMID: 18725978, 16982735, 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.
Color Health, Inc RCV000116012 SCV000537618 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 117 in the FHA domain of the CHEK2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant causes reduced kinase activity, reduced protein stability, incomplete phosphorylation of CHEK2 protein, defective DNA damage repair in a yeast based assay (PMID: 16835864, 16982735, 18725978, 22419737, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 12454775, 12610780, 18058223, 21244692, 22114986, 23555315, 25503501, 27553368, 27798748, 28503720, 30128536, 31263054), colorectal cancer (PMID: 30256826), and pancreatic cancer (PMID: 29922827, 29945567). This variant has been observed in eight breast cancer-affected individuals from three families, but the co-segregation with disease was inconclusive because the variant was absent in two individuals affected with breast cancer and one individual affected with colon cancer (PMID: 12610780). A large case-control study of European women has shown that this variant is associated with an increased risk of breast cancer with an OR of 2.26 (95% CI: 1.29 to 3.95). 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.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000204429 SCV000590881 likely pathogenic Familial cancer of breast 2017-03-22 criteria provided, single submitter clinical testing 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.
Counsyl RCV000204429 SCV000677766 likely pathogenic Familial cancer of breast 2017-02-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001263516 SCV000698796 likely pathogenic Malignant tumor of breast 2020-10-26 criteria provided, single submitter clinical testing 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). Eleven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (n=8) and pathogenic (n=3). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as a likely pathogenic.
PreventionGenetics,PreventionGenetics RCV000212414 SCV000806879 likely pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing
Mendelics RCV000204429 SCV000839495 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212414 SCV000889334 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212414 SCV000892319 likely pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258041 SCV001434869 pathogenic Breast cancer, susceptibility to; Prostate cancer, susceptibility to 2018-10-12 criteria provided, single submitter clinical testing 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.
Molecular Oncology Research Center,Barretos Cancer Hospital RCV001374534 SCV001438613 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-01 criteria provided, single submitter research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212414 SCV001447125 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000116012 SCV001448802 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000204429 SCV001499647 likely pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV001526815 SCV001737462 likely pathogenic Predisposition to cancer 2021-05-13 criteria provided, single submitter clinical testing 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000212414 SCV000691836 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000212414 SCV000784695 not provided not provided no assertion provided phenotyping only 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001263516 SCV001550444 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212414 SCV001742938 likely pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535470 SCV001749392 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000212414 SCV001799322 likely pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212414 SCV001808713 likely pathogenic not provided no assertion criteria provided clinical testing

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