Submissions for variant NM_007194.4(CHEK2):c.1100del (p.Thr367fs)

gnomAD frequency: 0.00181  dbSNP: rs555607708

Total submissions: 83

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212447	SCV000149889	pathogenic	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123265	SCV000166572	pathogenic	Familial cancer of breast	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115980	SCV000187220	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The c.1100delC (p.T367Mfs*15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (CHEK2 Breast Cancer Case-Control, 2004; Xiang, 2011; Weischer, 2012). However, a recent population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch, 2016). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt, 2016). This alteration has also been reported in male breast cancer cohorts (Leedom, 2016; Hallamies, 2017), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard, 2016). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu, 2001). Based on the available evidence, this alteration is classified as pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210137	SCV000266067	pathogenic	Breast and colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115980	SCV000292118	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000123265	SCV000488123	pathogenic	Familial cancer of breast	2016-01-20	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413386	SCV000492465	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212447	SCV000601142	pathogenic	not provided	2024-07-30	criteria provided, single submitter	clinical testing	The CHEK2 c.1100del (p.Thr367Metfs*15) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer and other cancers (PMIDs: 33471991 (2021), 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). In addition, this variant has been reported to be a founder mutation in Northern European countries (PMID: 15492928 (2004)). The frequency of this variant in the general population, 0.0087 (219/25124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212447	SCV000603087	pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615.
Fulgent Genetics, Fulgent Genetics	RCV000515188	SCV000611258	pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2017-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212447	SCV000691834	pathogenic	not provided	2024-03-04	criteria provided, single submitter	clinical testing	PP5, PS4_moderate, PVS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587467	SCV000698761	pathogenic	Li-Fraumeni syndrome	2019-07-25	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004556721	SCV000711416	pathogenic	CHEK2-related cancer predisposition	2015-03-10	criteria provided, single submitter	clinical testing	The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers.
GeneKor MSA	RCV000115980	SCV000821726	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042).
Mendelics	RCV000123265	SCV000839467	pathogenic	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735378	SCV000854533	pathogenic	Colitis; Inflammation of the large intestine; Hematochezia; Thrombocytopenia		criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291559	SCV000891024	pathogenic	Predisposition to cancer	2022-05-24	criteria provided, single submitter	clinical testing	The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance.
Illumina Laboratory Services, Illumina	RCV004556721	SCV000915968	pathogenic	CHEK2-related cancer predisposition	2017-04-27	criteria provided, single submitter	clinical testing	The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Academic Department of Medical Genetics, University of Cambridge	RCV000115980	SCV000992228	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000212447	SCV001245712	pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	CHEK2: PVS1, PP1:Strong, PS4:Moderate
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000123265	SCV001368134	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS3, PS4_STR, BS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV000123265	SCV001429484	pathogenic	Familial cancer of breast	2024-09-30	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4_MOD
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212447	SCV001447460	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000115980	SCV001449028	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-14	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212447	SCV001450042	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000123265	SCV001481483	pathogenic	Familial cancer of breast	2024-03-30	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000123265	SCV001499790	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212447	SCV002009513	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212447	SCV002019280	pathogenic	not provided	2020-10-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001270933	SCV002043388	pathogenic	Breast and/or ovarian cancer	2021-05-07	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000123265	SCV002061638	pathogenic	Familial cancer of breast	2021-11-01	criteria provided, single submitter	clinical testing	PVS1, PS4, PS3
AiLife Diagnostics, AiLife Diagnostics	RCV000212447	SCV002503454	pathogenic	not provided	2021-10-11	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225332	SCV002505157	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115980	SCV002537022	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212447	SCV002552006	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV002285140	SCV002575018	pathogenic	Familial cancer of breast; Malignant tumor of prostate; Colorectal cancer	2022-09-26	criteria provided, single submitter	research	PVS1, PS4, PS3_Supporting
MGZ Medical Genetics Center	RCV000123265	SCV002581843	pathogenic	Familial cancer of breast	2022-08-24	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002463641	SCV002758585	pathogenic	Colorectal cancer	2022-07-01	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PS3, PS4
Genetics and Molecular Pathology, SA Pathology	RCV000123265	SCV002761797	pathogenic	Familial cancer of breast	2019-12-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000005932	SCV003804673	pathogenic	Li-Fraumeni syndrome 2	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4_MOD
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000123265	SCV003806873	pathogenic	Familial cancer of breast	2022-10-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000115980	SCV003933671	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	case-control	Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies.
Myriad Genetics, Inc.	RCV000123265	SCV004020171	pathogenic	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002463641	SCV004027697	pathogenic	Colorectal cancer	2023-06-09	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4,PM2_SUP
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004556721	SCV004046245	pathogenic	CHEK2-related cancer predisposition	2024-09-10	criteria provided, single submitter	clinical testing	This variant is also referred to as c.1100delC (p.Thr367Metfs*15) in the literature. This frameshifting variant in exon 12 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on two large case-control studies, the relative risk (RR) for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). In addition, a meta-analysis reported a RR of 1.88 (95% C.I. 1.29-2.73) for CHEK2 c.1229del pathogenic variant and colorectal cancer (PMID: 23946381). This alteration has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). The c.1229del (p.Thr410MetfsTer15) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.21% (3467/1611346), including 5 homozygous individuals. It is enriched in the European (Finnish) population (MAF=0.87%). Based on the available evidence, c.1229del (p.Thr410MetfsTer15) is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388828	SCV004100720	pathogenic	Li-Fraumeni syndrome 1	2023-10-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4
Institute of Human Genetics, University Hospital of Duesseldorf	RCV002463641	SCV004171175	pathogenic	Colorectal cancer		criteria provided, single submitter	not provided
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	RCV000115980	SCV004174265	pathogenic	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research	ACMG/AMP, PVS1, PM2, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV003992185	SCV004812116	pathogenic	Malignant tumor of prostate	2024-03-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4_MOD
Institute of Immunology and Genetics Kaiserslautern	RCV000005932	SCV005043003	pathogenic	Li-Fraumeni syndrome 2	2024-04-24	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004577323	SCV005061419	pathogenic	Inherited breast cancer and ovarian cancer	2024-04-25	criteria provided, single submitter	clinical testing	PVS1,PS4
Department of Human Genetics, Hannover Medical School	RCV000005932	SCV005186168	pathogenic	Li-Fraumeni syndrome 2	2024-08-09	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004577323	SCV005196372	pathogenic	Inherited breast cancer and ovarian cancer	2024-06-14	criteria provided, single submitter	clinical testing	PVS1,PS4
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004691754	SCV005196385	pathogenic	NICE approved PARP inhibitor treatment	2024-08-12	criteria provided, single submitter	clinical testing	PVS1,PS4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212447	SCV005197499	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760381	SCV005368410	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-08-22	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PM1
Fulgent Genetics, Fulgent Genetics	RCV005025181	SCV005663105	pathogenic	Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer	2024-05-16	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000115980	SCV005689639	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1; PS4
OMIM	RCV003333692	SCV000026114	pathogenic	TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL	2006-11-01	no assertion criteria provided	literature only
Pathway Genomics	RCV000123265	SCV000189922	pathogenic	Familial cancer of breast	2014-07-24	no assertion criteria provided	clinical testing
Genome Sciences Centre, British Columbia Cancer Agency	RCV000488416	SCV000574565	pathogenic	Breast neoplasm; Leiomyosarcoma		no assertion criteria provided	clinical testing	Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer.
GenomeConnect, ClinGen	RCV000212447	SCV000607207	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. 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.
Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston	RCV000591014	SCV000692550	uncertain significance	Astrocytoma		flagged submission	clinical testing
True Health Diagnostics	RCV000115980	SCV000787999	pathogenic	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528801	SCV000806862	pathogenic	CHEK2-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic.
CZECANCA consortium	RCV001270933	SCV001451737	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354431	SCV001549046	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium	RCV001391208	SCV001593124	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212447	SCV001743466	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV004556721	SCV001749628	not provided	CHEK2-related cancer predisposition		no assertion provided	phenotyping only	Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001572630	SCV001792259	pathogenic	Breast carcinoma	2021-08-19	no assertion criteria provided	clinical testing	Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212447	SCV001798054	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212447	SCV001806916	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212447	SCV001906450	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212447	SCV001932166	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212447	SCV001954678	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212447	SCV001974642	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115980	SCV001977065	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770086	SCV002011794	pathogenic	Bone osteosarcoma	2021-07-26	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000500025	SCV002070848	pathogenic	Breast cancer, susceptibility to	2021-11-22	no assertion criteria provided	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619).
BRCAlab, Lund University	RCV000123265	SCV002588975	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000005932	SCV004171570	pathogenic	Li-Fraumeni syndrome 2	2023-11-24	no assertion criteria provided	clinical testing
Diagnostics Centre, Carl Von Ossietzky University Oldenburg	RCV003445511	SCV004174182	pathogenic	Ovarian neoplasm	2023-07-28	no assertion criteria provided	clinical testing	The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic.