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

gnomAD frequency: 0.00009  dbSNP: rs28909982

Total submissions: 44

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212414	SCV000149921	pathogenic	not provided	2019-12-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced auto-phosphorylation, protein instability, impaired kinase activity, and loss of CHEK2-mediated DNA damage response (Wu 2006, Sodha 2006, Chrisanthar 2008, Roeb 2012, Delimitsou 2019); Case control study in Europeans suggests this variant is associated with female breast cancer (Southey 2016); Observed in many individuals with CHEK2-related cancers (Sodha 2002, Kleibl 2008, Desrichard 2011, Le Calvez-Kelm 2011, Roeb 2012, Castera 2014, Moran 2017, Pinto 2016, Lu 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12454775, 18058223, 22114986, 21244692, 22419737, 24549055, 27798748, 27553368, 30128536, 27595995, 16835864, 16982735, 18725978, 30851065, 33158149, 31447099, 31206626, 31263054, 30303537, 30676620, 31090900, 30322717, 29922827, 15095295, 12610780, 30666157, 30426508, 29659569, 29945567, 30067863, 30256826, 28125075, 29439820, 28553140, 28709830, 28503720, 28008555, 28452373, 27498913, 28082821, 26681312, 23555315, 27751358, 15488637, 15385111, 23960188, 15818573)
Ambry Genetics	RCV000116012	SCV000183898	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing	The p.R117G variant (also known as c.349A>G), located in coding exon 2 of the CHEK2 gene, results from an A to G substitution at nucleotide position 349. The arginine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in many cancer cases including familial breast/ovarian, pancreatic and colorectal and prostate cancer cohorts (Sodha N et al. Br. J. Cancer. 2002 Dec;87:1445-8; Kleibl Z et al. Breast Cancer Res. Treat. 2008 Nov;112:159-64; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Moran O et al. Breast Cancer Res. Treat. 2017 Jan;161:135-142; Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Schutte M et al. Am. J. Hum. Genet. 2003 Apr;72:1023-8). This variant has also been reported to be a possible European founder variant leading to a significant increase in prostate cancer risk (Brandão A et al. Cancers (Basel). 2020 Nov;12(11)). Multiple functional studies have found that this variant is abnormal with respect to protein stability and kinase activity (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Chrisanthar R et al. PLoS One. 2008 Aug;3:e3062; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Delimitsou A et al. Hum. Mutat. 2019 May;40(5):631-648; Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). This alteration was also more frequent in breast cancer cases than controls in a study from the Breast Cancer Association Consortium (BCAC) (Southey MC et al. J. Med. Genet., 2016 12;53:800-811). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204429	SCV000262374	pathogenic	Familial cancer of breast	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 117 of the CHEK2 protein (p.Arg117Gly). This variant is present in population databases (rs28909982, gnomAD 0.02%). This missense change has been observed in individual(s) with CHEK2-related cancers (PMID: 12454775, 12610780, 21244692, 28503720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128071). 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: 16982735, 18725878, 22419737). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000116012	SCV000537618	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 117 in the FHA domain of the CHEK2 protein. 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 shown that this variant causes reduced kinase activity, reduced protein stability, incomplete phosphorylation of CHEK2 protein and defective DNA damage repair (PMID: 16835864, 16982735, 18725978, 22419737, 30851065, 34903604, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 12454775, 12610780, 18058223, 21244692, 22114986, 23555315, 25503501, 27553368, 27798748, 28503720, 30128536, 31263054, 33030641, 33326660, 33803639, 35264596, 36315097), colorectal cancer (PMID: 30256826), prostate cancer (PMID: 33158149), and pancreatic cancer (PMID: 29922827, 29945567). Large case-control studies have shown that this variant is associated with an increased risk of breast cancer (OR 2.26, 95% CI [1.29 to 3.95], PMID: 27595995; OR=2.936, 95%CI [1.823 to 4.73], PMID: 33471991; OR=2.83, 95% CI [2.35 to 3.41], PMID: 37449874). This variant has been identified in 32/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been shown to cause partial loss of CHEK2 protein function and is associated with an increased risk of breast cancer. Based on the available evidence, this variant is classified as Likely Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000204429	SCV000590881	likely pathogenic	Familial cancer of breast	2017-03-22	criteria provided, single submitter	clinical testing	This CHEK2 variant was identified in a female patient diagnosed with breast cancer at 38 years old, and whose mother also have had bilateral breast cancer at ages 40 and 42 years old. Mutation screening in BRCA1 and BRCA2 genes gave negative results.
Counsyl	RCV000204429	SCV000677766	likely pathogenic	Familial cancer of breast	2017-02-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263516	SCV000698796	pathogenic	Malignant tumor of breast	2022-06-09	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.349A>G (p.Arg117Gly) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant allele was found in 33/265114 control chromosomes at a frequency of 0.00012 (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in CHEK2 causing Breast Cancer (0.00012 vs 0.00031), allowing no conclusion about variant significance. The variant, c.349A>G, has been reported in the literature in multiple individuals affected with cancer including breast cancer, pancreatic cancer, colorectal cancer and prostate cancer (but also in controls) (Hu_2018, Lu_2018, Martin-Morales_2018, Paulo_2018, Rummel_2017, Pinto_2016, Southey_2016), with limited cosegregation information. In one study, in 3 families, 8 transmissions of the variant allele and 2 transmissions of the reference allele to affected individuals was reported (Schutte_2003). The variant has also been reported in studies that included cohorts of comprehensively genotyped patients with early onset breast cancer meeting the NCCN guidelines (Rummel_2017), and a family history of breast cancer (Pinto_2016; Moran_2017, Lu_2018). A case-control study showed evidence of association with breast cancer (OR = 2.03; Southey_2016) but no association with prostate and ovarian cancer, suggesting this might be a risk variant. FLOSSIES database reports the variant in 2 women older than age 70 years who have never had cancer. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.891_899delAACAGTTGTinsGATACTTCAG, p.Thr298Ilefs; CHEK2 c.1100delC, p.Thr367fsX15 (Susswein_2015); APC c.426_427delAT, p.Leu143AlafsX4 at our laboratory). However, as co-occurrence with other pathogenic variants is not mutually exclusive in cancer probands, this is not entirely supportive of a benign role of this variant. Functional in vitro and in vivo studies showed that p.R117G is incompletely phosphorylated and is not efficiently activated in response to DNA damage, showing minimal kinase activity when studied in isolation, however, it can dimerize efficiently to CHEK2 wild-type without strongly affecting the wild-type CHEK2 activity (Roeb_2012, Chrisanthar_2008, Sodha_2006, Wu_2006). Twenty ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (n=16) and pathogenic (n=4). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000204429	SCV000839495	likely pathogenic	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212414	SCV000889334	pathogenic	not provided	2022-03-12	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 31263054 (2019), 31206626 (2019), 31090900 (2019), 30303537 (2019), 30426508 (2018), 30128536 (2018), 28709830 (2017), 28503720 (2017), 27553368 (2016), 25503501 (2015)), prostate cancer (PMIDs: 29659569 (2018), 29439820 (2018)), and pancreatic cancer (PMIDs: 29945567 (2018), 29922827 (2018)). In addition, families show evidence of co-segregation with breast cancer (PMID: 12610780 (2003)). Functional studies in the published literature report this variant causes loss of CHEK2 activity (PMIDs: 30851065 (2019), 22419737 (2012), 18725978 (2008), 16982735 (2006), 16835864 (2006)). The frequency of this variant in the general population, 0.00019 (24/128958 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212414	SCV000892319	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	CHEK2: PP1:Strong, PS4, PP3, PS3:Supporting, BP1
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258041	SCV001434869	pathogenic	Breast cancer, susceptibility to; Prostate cancer susceptibility	2018-10-12	criteria provided, single submitter	clinical testing	The c.349A>G(p.Arg117Gly) variant in the CHEK2 gene (seen 31 times in gnomAD) has been observed in multiple unrelated probands and segregated in one family with BRCA1/2 negative breast cancer (PMID 12454775, 12610780, 18058223, 27595995, 27553368, 27798748). Although not validated for clinical use, the in silico programs predict this variant to be damaging. Experimental studies are consistent with this variant resulting in disruption of CHEK2 function (PMID 16982735, 16835864, 22419737). Therefore, this c.349A>G (p.Arg117Gly) variant in the CHEK2 gene is classified as pathogenic.
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374534	SCV001438613	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-01	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212414	SCV001447125	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000116012	SCV001448802	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-04-18	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000204429	SCV001499647	likely pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001526815	SCV001737462	likely pathogenic	Predisposition to cancer	2021-05-13	criteria provided, single submitter	clinical testing	The CHEK2 c.349A>G (p.Arg117Gly) missense change has a maximum frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/22-29121326-T-C?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). Several functional studies suggest that this variant is pathogenic, demonstrating a strongly reduced CHEK2-mediated DNA damage response, impaired kinase activity, and incomplete phosphorylation (PS3; PMID: 18725978, 22419737, 30851065, 16835864, 16982735). This variant has been identified in many cancer cases including familial breast/ovarian, prostate, pancreatic, colorectal, as well as other cancer types (PMID: 12454775, 15095295, 21244692, 26681312, 28125075, 29439820, 29659569, 29439820, 29945567, 30322717, 30256826, 28709830, 30426508, 31090900, 31263054, 31206626, 32906215, 30676620, 32906215). A case-control study showed evidence of association with breast cancer (PS4; OR = 2.26; PMID: 27595995), but no association with prostate and ovarian cancer. In addition, the variant segregated with breast cancer in three families, although it was not identified in all affected family members (PMID: 12610780) This variant is present 2x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PS3, PS4, PP3, BS2_supporting.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212414	SCV002009501	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001787918	SCV002030095	likely pathogenic	Li-Fraumeni syndrome 2	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798355	SCV002043402	likely pathogenic	Breast and/or ovarian cancer	2023-01-18	criteria provided, single submitter	clinical testing
DASA	RCV004556728	SCV002318957	likely pathogenic	CHEK2-related cancer predisposition	2022-03-25	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18725978; 16982735; 22419737) - PS3_moderate. The c.349A>G;p.(Arg117Gly) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 128071; PMID: 12454775; PMID: 12610780; PMID: 21244692; PMID: 28503720) -PS4. The variant is present at low allele frequencies population databases (rs28909982 – gnomAD 0.001132%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic
Sema4, Sema4	RCV000116012	SCV002537425	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-30	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000204429	SCV002761585	likely pathogenic	Familial cancer of breast	2021-04-26	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000204429	SCV002762811	likely pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PS3, PS4_STR
Fulgent Genetics, Fulgent Genetics	RCV005003477	SCV002806805	likely pathogenic	Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer	2024-06-07	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003114263	SCV003799122	pathogenic	CHEK2-related disorder	2022-10-03	criteria provided, single submitter	clinical testing	PS3, PS4, PP3
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV001787918	SCV003836493	pathogenic	Li-Fraumeni syndrome 2	2023-03-06	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing.
Myriad Genetics, Inc.	RCV000204429	SCV004020195	likely pathogenic	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000204429	SCV004215845	likely pathogenic	Familial cancer of breast	2024-03-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212414	SCV004242520	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004556728	SCV004801674	likely pathogenic	CHEK2-related cancer predisposition	2018-05-15	criteria provided, single submitter	clinical testing	The CHEK2 c.349A>G p.(Arg117Gly), also referred to c.478A>G (Arg160Gly), missense variant has been identified in individuals with a phenotype consistent with CHEK2-related cancer susceptibility. In two individuals, other pathogenic BRCA2 and CHEK2 variants were also identified (Sodha et al. 2002; Schutte et al. 2003; Le Calvez-Kelm et al. 2011; Southey et al. 2016; Susswein et al. 2016). In a large case-control study, Southey et al. (2016) showed that the p.(Arg117Gly) variant was significantly associated with breast cancer in European women (odds ratio of 2.26). In this study, odd ratios were not statistically significant for prostate cancer or ovarian cancer. The variant segregated with breast cancer in one family whereas in two families incomplete segregation was observed whereby two affected individuals did not carry the variant (Schutte et al. 2003). The highest frequency of this allele in the Genome Aggregation Database is 0.000186 in the European (non-Finnish) population (version 2.1.1). Functional studies in cells lines demonstrated reduced protein expression and stability, and impaired phosphorylation and kinase activity of the variant protein when compared to wildtype protein. However, the variant protein dimerized efficiently to wildtype CHEK2 (Sodha et al. 2006; Wu et al. 2006; Chrisanthar et al. 2008). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.349A>G p.(Arg117Gly) variant is classified as likely pathogenic for CHEK2-related breast cancer susceptibility.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212414	SCV005197506	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000116012	SCV005689640	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212414	SCV000691836	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000212414	SCV000784695	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV003114263	SCV000806879	likely pathogenic	CHEK2-related disorder	2024-06-04	no assertion criteria provided	clinical testing	The CHEK2 c.349A>G variant is predicted to result in the amino acid substitution p.Arg117Gly. This is a well-documented variant reported in multiple individuals with cancers of breasts, colon, skin, kidneys, thyroid, ovaries and prostate gland (Table S1, Susswein et al. 2016. PubMed ID: 26681312; Southey et al. 2016. PubMed ID: 27595995). Earlier, Schutte and colleagues had described this variant as having no major contribution to susceptibility to breast cancer (Schutte et al. 2003. PubMed ID: 12610780). However, more recently the authors reported it to be associated with increased risk for breast cancer, but not for prostate and ovarian cancers (Southey et al. 2016. PubMed ID: 27595995). Several functional studies on this variant have indicated impaired CHEK2 functions, specifically the kinase activity and DNA damage response (Chrisanthar et al. 2008. PubMed ID: 18725978; Roeb et al. 2012. PubMed ID: 22419737). The Arg117 residue, located within the forkhead-associated domain of the CHEK2 protein, has been highly conserved during evolution (http://www.uniprot.org/uniprot/O96017). This variant is listed in the ClinVar database with interpretations of likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128071/). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001263516	SCV001550444	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Arg117Gly variant was identified in 55 of 88752 proband chromosomes (frequency: 0.0006) from individuals or families with hereditary breast and ovarian cancer (Desrichard 2011, Kleibl 2008, Moran 2017, Pinto 2016, Schutte 2003, Sodha 2002, Southey 2016, Wu 2006). The variant was also identified in dbSNP (ID: rs28909982) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx and Mayo Clinic; and as likely pathogenic by Ambry Genetics, Invitae, Color Genomics, University Hospital of Geneva, and Counsyl), MutDB, and Zhejiang Colon Cancer Database (4x). The variant was not identified in the Cosmic database. The variant was identified in control databases in 31 of 276970 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24030 chromosomes (freq: 0.00008), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 4 of 34418 chromosomes (freq: 0.0001), European in 22 of 126468 chromosomes (freq: 0.0002), Finnish in 2 of 25792 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg117Gly variant has been extensively studied in the literature. In vitro studies have demonstrated that the Arg117Gly variant has strongly reduced kinase activity (Chrisanthar 2008). Multiple studies found that following DNA damage with ionizing radiation, the variant protein demonstrated greatly reduced CHEK2 kinase activity (Wu 2006, Roeb 2012, Le Calvez-Kelm 2011). In addition, studies have shown that the protein encoded by this allele is phosphorylated by ATM in response to DNA damage, shows slightly to markedly reduced autophosphorylation, probably fails to oligomerize, and has severely compromised kinase activity. Sodha (2006) also concluded through bioinformatic analysis that the variant is likely to be deleterious and functional studies showed that the variant protein is less stable than the wild type protein. The p.Arg117Gly residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212414	SCV001742938	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV004556728	SCV001749392	not provided	CHEK2-related cancer predisposition		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 03-13-2018 by 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212414	SCV001799322	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212414	SCV001808713	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212414	SCV001906416	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212414	SCV001958164	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212414	SCV001963773	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001787918	SCV004041663	likely pathogenic	Li-Fraumeni syndrome 2	2023-10-09	no assertion criteria provided	clinical testing