Submissions for variant NM_007194.4(CHEK2):c.1421G>A (p.Arg474His)

gnomAD frequency: 0.00007  dbSNP: rs121908706

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000114766	SCV000149909	likely pathogenic	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased autophosphorylation, kinase activity, and protein stability (PMID: 31050813, 34903604, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1550G>A p.(R517H); This variant is associated with the following publications: (PMID: 26506619, 25452441, 31050813, 30303537, 30333958, 30374176, 31422574, 25186627, 30613976, 33471991, 29522266, 25085752, 34903604, 35534704, 34326862, 36288950, 37449874, 22419737, 19782031)
Ambry Genetics	RCV000116000	SCV000172827	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	The p.R474H variant (also known as c.1421G>A), located in coding exon 12 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1421. The arginine at codon 474 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple cohorts of individuals diagnosed with lymphoma, breast, colon and/or ovarian cancer (Havranek O et al. PLoS ONE. 2015 Oct;10:e0140819; Tung N et al. Cancer, 2015 Jan;121:25-33; Brovkina OI et al. Front Oncol. 2018 Oct 2;8:421; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439; Güleç Ceylan G et al. Tohoku J Exp Med, 2022 Nov;258:319-325). This variant was non-functional in an in vitro kinase assay and a human cell-based kinase assays measuring KAP1 phosphorylation and CHK2 autophosphorylation (Kleiblová P et al. Klin Onkol, 2019;32:36-50; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). In a mouse embryonic stem cell-based system, this alteration was found to be damaging to Kap1 phosphorylation (Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206096	SCV000259372	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 474 of the CHEK2 protein (p.Arg474His). This variant is present in population databases (rs121908706, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and non-Hodgkin lymphoma (PMID: 25186627, 25452441, 26506619, 30303537, 30333958, 30613976, 31050813, 34903604). This variant is also known as p.Arg517His. ClinVar contains an entry for this variant (Variation ID: 126910). 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: 31050813, 34903604). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000114766	SCV000609072	likely pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116000	SCV000684591	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 474 of the CHEK2 protein. This variant impacts a highly conserved arginine in the kinase domain of the protein (PMID: 15060014, 19782031). 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 reported that this variant impacts CHEK2 function in kinase assays and DNA damage response performed in mouse embryonic stem cells, yeast and in vitro models (PMID: 30851065, 31050813, 34903604). This variant has been detected in a breast cancer case-control meta-analysis in 18/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000183). This variant also has been reported in individuals affected with breast cancer (PMID: 25186627, 25452441, 29522266, 30303537), a suspected hereditary breast and ovarian cancer family (PMID: 30333958), an individual affected with non-Hodgkin lymphoma (PMID: 26506619) and an individual without cancer diagnosis (PMID: 31422574). This variant has been identified in 19/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Counsyl	RCV000206096	SCV000785113	uncertain significance	Familial cancer of breast	2017-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000114766	SCV000888106	uncertain significance	not provided	2020-05-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000206096	SCV001251426	likely pathogenic	Familial cancer of breast	2024-05-22	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM5,PS4_SUP
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116000	SCV004014885	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000206096	SCV004015278	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	The p.R474H variant (also known as c.1421G>A), located in coding exon 12 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1421. The arginine at codon 474 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a familial breast and ovarian cancer patient (reported as c.1550G>A, p.Arg517His under reference sequence NM_001005735.1) and reported in the germline of 1/340 non-Hodgkin lymphoma patients and in 0/445 non-cancer controls (Havranek O et al. PLoS ONE. 2015 Oct;10:e0140819; Brovkina OI et al. Front Oncol. 2018 Oct 2;8:421). This amino acid position is highly conserved in available vertebrate species. This variant has an entry in ClinVar with 9 submissions, one pathogenic, on “not provided”, and 7 uncertain significance, one star. Alternative variant chr22:29090060 C⇒A (Arg474Leu) is classified Likely Pathogenic, 0 stars, by ClinVar In addition, this alteration is predicted to be pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 1 benign prediction from PrimateAI. Therefore, this variant is classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000114766	SCV004024324	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003387763	SCV004176000	likely pathogenic	Li-Fraumeni syndrome 2	2023-11-03	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM5,PS4_SUP
Baylor Genetics	RCV000206096	SCV004217636	uncertain significance	Familial cancer of breast	2024-02-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492448	SCV004240446	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700414	SCV005203500	uncertain significance	not specified	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1421G>A (p.Arg474His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233796 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1421G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, or an unspecified hereditary cancer (e.g. Girard_2019, de Oliveira_2022, Kleiblova_2019, Couch_2015, Rizzolo_2019, Brovkina_2018, Bhai_2021, Akcay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <20% of normal kinase activity (Kleiblova_2019, Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 34326862, 34903604, 30333958, 25452441, 30303537, 26506619, 31050813, 30613976, 30374176, 25186627, 35534704). ClinVar contains an entry for this variant (Variation ID: 126910). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	RCV000114766	SCV000148661	not provided	not provided		no assertion provided	not provided
Myriad Genetics, Inc.	RCV000206096	SCV004020183	likely benign	Familial cancer of breast	2023-03-09	flagged submission	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003387763	SCV004099435	uncertain significance	Li-Fraumeni syndrome 2	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737196	SCV005360329	uncertain significance	CHEK2-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The CHEK2 c.1421G>A variant is predicted to result in the amino acid substitution p.Arg474His. This variant has been reported in an individual with non-Hodgkin lymphoma (Havranek et al. 2015. PubMed ID: 26506619), individuals with breast cancer (Couch et al. 2015. PubMed ID: 25452441, Table S6; Tung et al. 2015. PubMed ID: 25186627, Supp. Info; Girard et al. 2019. PubMed ID: 30303537, Table S3), and an individual with ovarian cancer (Kleiblova et al. 2019. PubMed ID: 31050813, Tables 1 and S3, Patient 1380).  It has also been reported in an individual with a family history of hereditary breast and/or ovarian cancer (HBOC), but was also found in control individuals (Brovkina et al. 2018. PubMed ID: 30333958, Table 3, referred to as c.1550G>A, p.Arg517His). A variant interpretation study interpreted this variant as uncertain significance (Tsai et al. 2019. PubMed ID: 30374176, Table S1). Functional studies suggest this variant may impair CHK2 kinase catalytic activity (Kleiblova et al. 2019. PubMed ID: 31050813, Figure 2, Table S2). This variant has been reported at a frequency of ~0.02% in individuals of African origin in the gnomAD database. There are conflicting interpretations of pathogenicity ranging from likely pathogenic to likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126910/). Based on these observations, the c.1421G>A variant is classified as uncertain.