ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1100del (p.Thr367fs) (rs555607708)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 42
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212447 SCV000149889 pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.1100delC at the cDNA level and p.Thr367MetfsX15 (T367MfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATTA[delC]TGAT. The deletion causes a frameshift, which changes a Threonine to a Methionine at codon 367 and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. In vitro functional analyses have found that CHEK2 c.1100delC results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (Lee 2001, Wu 2001). Although present in approximately 0.5 - 1% of healthy European individuals (Meijers-Heijboer 2002, Neuhausen 2004, Wasielewski 2009, Schmidt 2016), based on functional studies and the case-control data summarized below, CHEK2 c.1100delC is considered pathogenic. CHEK2 c.1100delC is associated with an increased risk for certain cancers, including breast, colon, prostate, and others as described below. The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in CHEK2 (NCCN). Breast Cancer: CHEK2 c.1100delC is considered a breast cancer susceptibility allele in Western Populations by The CHEK2 Breast Cancer Case-Control Consortium and is observed at higher frequencies among breast cancer cases, with an odds ratio (OR) of approximately 2.3-3.3 in sporadic or unselected cases, and 3.1-4.2 in familial cases, depending on strength of family history (The CHEK2 Breast Cancer Consortium 2004, Desrichard 2011, Schmidt 2016, Couch 2017, Decker 2017). Compared with breast cancer patients without CHEK2 c.1100delC, women who carried the pathogenic variant had higher rates of a second breast cancer, particularly if the first was estrogen-receptor positive (Weischer 2012, Muranen 2016). Although previous studies have not observed a statistically significant association with male breast cancer (Syrjakoski 2003, Ohayon 2004, Neuhausen 2004, Falchetti 2008), recent reports, including a large meta-analysis, indicate a statistically higher incidence of breast cancer in men with c.1100delC (Hallamies 2017, Pritzlaff 2017, Liang 2018). Colon and Prostate Cancer: Earlier studies did not show a statistically significant association for CHEK2 c.1100delC with colorectal cancer (CRC) (Kilpivaara 2003, Djureinovic 2006, Kleibl 2008). However, data from recent large meta-analyses may suggest an association supported by a modestly elevated OR (approximately 1.8) in unselected CRC cases (Ma 2014, Katona 2017). CHEK2 c.1100delC has previously been associated with familial prostate cancer with varying odds ratios and wide confidence intervals (Seppala 2003, Cybulski 2006). A meta-analysis of five studies with independent data reported an increased risk for prostate cancer in men with CHEK2 c.1100delC in both unselected (OR=1.98) and familial (OR=3.39) cases (Hale 2014). Additionally, the relative risk (RR=3.1; p=0.002) of CHEK2 alterations, especially truncating variants, in unselected patients with metastatic prostate cancer was shown to be elevated (Pritchard 2016). Other Cancers: Case-control studies have found significant associations for CHEK2 c.1100delC and other truncating variants with papillary thyroid cancer, gastric cancer, and renal cancer (Teodorczyk 2013, Siolek 2015, Naslund-Koch 2016, Carlo 2018).
Invitae RCV000123265 SCV000166572 pathogenic Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100del), causing a frameshift at codon 367. This creates a premature translational stop signal (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 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115980 SCV000187220 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The c.1100delC pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon (p.T367Mfs*15). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu X et al. J. Biol. Chem. 2001 Jan;276(4):2971-4). Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (The CHEK2 Breast Cancer Case-Control Consortium. Am. J. Hum. Genet. 2004 Jun;74(6):1175-82; Xiang HP et al. Eur. J. Cancer. 2011 Nov;47(17):2546-51; Weischer M et al. J. Invest. Dermatol. 2012 Feb;132(2):299-303). 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 C et al. J. Clin. Oncol. 2016 Apr;34(11):1208-16). 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 MK et al. J. Clin. Oncol. 2016 Aug;34(23):2750-60). This alteration has also been reported in male breast cancer cohorts (Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407; Hallamies S et al. BMC Cancer 2017 Sep;17:620), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 Health, Inc RCV000115980 SCV000292118 pathogenic Hereditary cancer-predisposing syndrome 2020-10-12 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 is well documented as a disease-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
Genetic Services Laboratory, University of Chicago RCV000500025 SCV000594116 pathogenic Breast cancer, susceptibility to 2016-08-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212447 SCV000601142 pathogenic not provided 2020-07-21 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000041 SCV000603087 pathogenic none provided 2020-02-20 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; Osteosarcoma; Malignant tumor of prostate 2017-05-18 criteria provided, single submitter clinical testing
Laboratory of Molecular Neuropathology,The University of Texas Health Science Center at Houston RCV000591014 SCV000692550 uncertain significance Astrocytoma criteria provided, single submitter clinical testing
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,Partners HealthCare Personalized Medicine RCV000615743 SCV000711416 pathogenic CHEK2-Related Cancer Susceptibility 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.
PreventionGenetics,PreventionGenetics RCV000212447 SCV000806862 pathogenic not provided 2016-05-31 criteria provided, single submitter clinical testing
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
CHLA 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 Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761109 SCV000891024 pathogenic Diffuse intrinsic pontine glioma 2016-10-05 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761147 SCV000891063 pathogenic B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified 2016-11-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000615743 SCV000915968 pathogenic CHEK2-Related Cancer Susceptibility 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 Praxis fuer Humangenetik Tuebingen RCV000212447 SCV001245712 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000123265 SCV001368134 pathogenic Familial cancer of breast 2018-09-25 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS4.
Institute of Human Genetics, University of Leipzig Medical Center RCV000123265 SCV001429484 uncertain significance Familial cancer of breast 2018-03-02 criteria provided, single submitter clinical testing
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 Karolinska University Hospital,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 2019-07-17 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 10617473, 23329222, 23415889, 22058428, 26332814, 24723567, 29146883]
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000123265 SCV001499790 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
OMIM RCV000005932 SCV000026114 pathogenic Li-Fraumeni syndrome 2 2006-11-01 no assertion criteria provided literature only
OMIM RCV000500025 SCV000026115 risk factor Breast cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005934 SCV000026116 risk factor Prostate cancer, susceptibility to 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000212447 SCV000691834 pathogenic not provided no assertion criteria provided clinical testing
True Health Diagnostics RCV000115980 SCV000787999 pathogenic Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
CZECANCA consortium RCV001270933 SCV001451737 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
OMIM RCV001290296 SCV001478327 risk factor Colorectal cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.