ClinVar Miner

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

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Total submissions: 13
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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 2018-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Structural Evidence
Invitae RCV000204429 SCV000262374 likely pathogenic Familial cancer of breast 2019-01-09 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 reported 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 RCV000116012 SCV000537618 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America RCV000204429 SCV000698796 likely pathogenic Familial cancer of breast 2019-03-13 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 34/290848 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; APC c.426_427delAT, p.Leu143AlafsX4) (Susswein_2015 and internal testing data). 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). Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (7x) and once as pathogenic. 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 2018-09-30 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing 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.

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