Submissions for variant NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)

gnomAD frequency: 0.00034  dbSNP: rs200050883

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587890	SCV000149905	likely benign	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive/conflicting: demonstrates intermediate/reduced kinase activity in some studies while others, including a human-cell based assay, show activity comparable to wildtype (Bell et al., 2007; Delimitsou et al., 2019; Kleiblova et al., 2019; Boonen et al., 2022); Observed in individuals with a personal and/or family history of breast, prostate, or colorectal cancer (Seppala et al., 2003; Bell et al., 2007; Tischkowitz et al., 2008; Baloch et al., 2014; Tung et al., 2015; Kayser et al., 2018; Fanale et al., 2020; Grasel et al., 2020; Moradian et al., 2021; Paduano et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14612911, 15087378, 28828701, 28776603, 28873162, 24390236, 17721994, 18571837, 23960188, 21244692, 27067391, 26787654, 28553140, 25186627, 27153395, 27498913, 27878467, 28452373, 19768534, 29335925, 27595995, 27443514, 29987844, 29484706, 30344923, 28301460, 30851065, 29875428, 29522266, 31050813, 31398194, 31159747, 28779002, 31220302, 33134171, 33322746, 32854451, 33558524, 27009842, 32906215, 30613976, 27535533, 34903604, 34347074, 22419737, 19782031, 35886069, 33840814)
Ambry Genetics	RCV000115996	SCV000172942	likely benign	Hereditary cancer-predisposing syndrome	2020-12-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000199565	SCV000254923	likely benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000199565	SCV000489071	uncertain significance	Familial cancer of breast	2016-08-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115996	SCV000537526	likely benign	Hereditary cancer-predisposing syndrome	2019-08-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587890	SCV000601150	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 36653541 (2023), 35886069 (2022), 33558524 (2021), 33134171 (2020), 31050813 (2019), 29484706 (2018), 29335925 (2018), 28779002 (2017), 25186627 (2015), 24390236 (2014), 21244692 (2011)), endometrial cancer (PMID:27443514 (2016)), colorectal cancer (PMID: 29987844 (2018)), and prostate cancer (PMIDs: 18571837 (2008), 17721994 (2007), 14612911 (2003)). This variant has also been identified in healthy control individuals (PMIDs: 36653541 (2023), 31050813 (2019), 30303537 (2019), 28779002 (2017), 21244692 (2011), 17721994 (2007)), and reported to co-occur with deleterious variants in the MRE11 and MSH2 genes (PMIDs: 33134171 (2020), 27443514 (2016)). Case-control studies suggest this variant is associated with prostate cancer risk but not breast cancer risk (PMIDs: 27595995 (2016), 36653541 (2023)). In addition, experimental studies indicate this variant has neutral to intermediate effects on CHEK2 protein function (PMIDs: 34903604 (2022), 31050813 (2019), 30851065 (2019), 17721994 (2007)). The frequency of this variant in the general population, 0.0013 (32/25122 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000515311	SCV000611451	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200982	SCV000698770	likely benign	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1312G>T (p.Asp438Tyr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 261860 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5- fold the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the frequency in gnomAD and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between CHEK2 and its multiple overlapping pseudogenes. This variant has also been reported among 7 women older than 70 years who have never had cancer as reported in the FLOSSIES database. c.1312G>T, has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer, but also in controls and in a family where it did not segregate with disease (examples- Baloch_2013, Bell_2007, LeCalvez-Kelm_2011, Seppala_2003, Tischkowitz_2008, Young_2016, Yadav_2016, Tung_2015, Maxwell_2016, Fostira_2018, Scarpetta_2019). Case control approaches indicated no significant risk association for breast cancer, but a slightly elevated risk for prostate cancer (Le Calvez-Kelm_2011, Southey_2016). These data thus do not allow any conclusion about variant significance. At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.1697del, p.Asn566IlefsX24), providing supporting evidence for a benign role (Ring_2016). In a mammalian cell based kinase-assay the variant protein showed about 70% reduction in activity (Bell_2007), whereas in a yeast based DNA-damage assay the variant showed similar function to the wild type supporting a benign outcome (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24390236, 17721994, 15087378, 30851065, 31811167, 29335925, 30303537, 33134171, 29484706, 25231023, 29987844, 21244692, 30322893, 27153395, 33558524, 27443514, 31512090, 14612911, 27595995, 18571837, 31159747, 25186627, 29875428, 27878467, 31214250, 26787654, 28828701, 23960188). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance (n=15) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003389694	SCV000806866	uncertain significance	CHEK2-related condition	2024-01-30	criteria provided, single submitter	clinical testing	The CHEK2 c.1312G>T variant is predicted to result in the amino acid substitution p.Asp438Tyr. This variant has been reported in individuals with a history of breast, prostate, and colorectal cancers; but has also been reported in unaffected control individuals (Baloch et al. 2014. PubMed ID: 24390236; Supplementary Table 1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Tischkowitz et al. 2008. PubMed ID: 18571837; Kleiblova et al. 2019. PubMed ID: 31050813; Moradian et al. 2021. PubMed ID: 33558524; Biscaglia et al. 2022. PubMed ID: 34347074). Functional studies have shown this variant impacts CHEK2 kinase activity by 70% when compared to wild-type protein; however, it is unclear whether this is sufficient to contribute to disease (Bell et al. 2007. PubMed ID: 17721994). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091178-C-A). It has conflicting interpretations in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128056/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneKor MSA	RCV000115996	SCV000821989	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492502	SCV000839460	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587890	SCV000892301	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CHEK2: BP1, BP4, BS2
Illumina Laboratory Services, Illumina	RCV001147975	SCV001308835	uncertain significance	CHEK2-Related Cancer Susceptibility	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	RCV000115996	SCV001482297	uncertain significance	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research
Baylor Genetics	RCV001294021	SCV001482780	uncertain significance	Li-Fraumeni syndrome 2	2019-10-12	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587890	SCV002009508	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798350	SCV002043391	uncertain significance	Breast and/or ovarian cancer	2023-02-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200982	SCV002070844	uncertain significance	not specified	2019-01-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200982	SCV002761098	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Research Unit of Translational Medicine, University of Oulu	RCV000199565	SCV003930315	likely benign	Familial cancer of breast	2022-11-22	criteria provided, single submitter	research	The frequency of p.Asp438Tyr variant in CHEK2 among Northern Finnish breast cancer cases was 0.6% (14/2284) and nearly equal in geographically matched healthy population controls (0.8%, 10/1299) in a study by Kumpula et al. (2023). Similar carrier frequencies in the studied cases and the general population argue against association of CHEK2 p.Asp438Tyr with increased breast cancer risk. Therefore the variant can be classified as likely benign.
Myriad Genetics, Inc.	RCV000199565	SCV004020177	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	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].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483481	SCV004231867	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	curation	Results from functional assays as well as predictions are contradictory. According to the ACMG standard criteria we chose this criterium: BS1 (strong benign): gnomAD v3.1.2 (non-cancer): AF: 0.0005092 + 1 x hom
Revvity Omics, Revvity	RCV000587890	SCV004235063	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000587890	SCV000986776	not provided	not provided		no assertion provided	phenotyping only	The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 03-29-2018 by Lab or GTR ID Northwell Health Laboratories. Variant interpreted as Uncertain significance and reported, most recently, on 12/04/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. 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.
Center of Medical Genetics and Primary Health Care	RCV000199565	SCV000987292	uncertain significance	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: Pkinase domain (M265-529L aa) which contains the catalytic function of protein kinases. Hot-spot has 21 non-VUS coding variants (7 pathogenic and 14 benign), pathogenicity = 33.3%, proximity score 3.967 > threshold 2.472. PP1 Pathogenic Supporting: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP2 Pathogenic Supporting: 30 out of 48 non-VUS missense variants in gene CHEK2 are pathogenic = 62.5% > threshold of 51.0%, and 308 out of 1,604 clinically reported variants in gene CHEK2 are pathogenic = 19.2% > threshold of 12.0%. PP1 Pathogenic Supporting: 2 patients are sibs (sisters) who share the same variant. BP4 Benign Supporting: 6 benign predictions from DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 5 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MutationTaster and SIFT and the position is not conserved." Therefore, this variant was classified as a Variant of Unknown Significance.
Center of Medical Genetics and Primary Health Care	RCV001269492	SCV001449146	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356041	SCV001551095	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The CHEK2 p.Asp438Tyr variant was identified in 4 of 1332 proband chromosomes (frequency: 0.003) from Pakistani, Finnish, Polish and Ashkenazi Jewish individuals or families with breast, early onset breast and prostate, or hereditary prostate cancer and was not identified in 590 control chromosomes from healthy individuals (Baloch 2014, Seppala 2003, Tischkowitz 2008, Bell 2007). The variant was identified in dbSNP (ID: rs200050883) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics), and the Zhejiang Colon Cancer Database (14x, co-occurring with CHEK2 c.1100delC). The variant was not identified in Cosmic. The variant was identified in control databases in 108 of 276806 chromosomes at a frequency of 0.0004 (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations: European in 57 of 126326 chromosomes (frequency: 0.0005), Finnish in 33 of 25792 chromosomes (frequency: 0.001), African in 3 of 24032 chromosomes (frequency: 0.0001), Other in 4 of 6456 chromosomes (frequency: 0.0006), Latino in 2 of 34404 chromosomes (frequency: 0.00006), and South Asian in 9 of 30776 chromosomes (frequency: 0.0003). The variant occurs in the catalytic domain of the CHEK2 protein and in vitro analysis of kinase activity showed the variant had a 70% decrease in activity compared to wildtype (Baloch 2014, Bell 2007). The p.Asp438 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587890	SCV001808572	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587890	SCV001905700	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587890	SCV001952270	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587890	SCV001962749	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587890	SCV001980184	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587890	SCV002036312	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001147975	SCV004228603	not provided	CHEK2-Related Cancer Susceptibility		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 04-04-2017 by Lab 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.