Submissions for variant NM_007194.4(CHEK2):c.277del (p.Trp93fs)

dbSNP: rs786203458

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166773	SCV000217586	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	The c.277delT pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 277, causing a translational frameshift with a predicted alternate stop codon (p.W93Gfs*17). This mutation has been reported in multiple individuals with breast cancer (Lhota F et al. Clin. Genet. 2016 Oct;90:324-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kleiblova P et al. Int J Cancer 2019 10;145(7):1782-1797; Cybulski C et al. J Clin Oncol 2011 Oct;29(28):3747-52). 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.
Invitae	RCV000197766	SCV000253900	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp93Glyfs*17) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26822949, 30093976). ClinVar contains an entry for this variant (Variation ID: 187085). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000223102	SCV000279224	pathogenic	not provided	2022-08-01	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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30303537, 26681312, 26822949, 27751358, 30093976, 31050813, 30875412, 34903604)
Counsyl	RCV000197766	SCV000488948	pathogenic	Familial cancer of breast	2016-08-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166773	SCV000684623	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 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. To our knowledge, this variant has been reported in individuals affected with breast cancer in the literature (PMID: 26681312, 26822949, 30875412, 30093976, 31050813, 30303537). This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223102	SCV001134163	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	The CHEK2 c.277del (p.Trp93Glyfs*17) 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 multiple individuals with breast cancer (PMID: 26822949 (2016), 30093976 (2018), 30128536 (2018), 30303537 (2019), 33471991 (2021)), including an individual with both breast cancer and melanoma (PMID: 26681312 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000223102	SCV001245719	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	CHEK2: PVS1, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV002294059	SCV001440945	pathogenic	Li-Fraumeni syndrome 2	2022-10-07	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Genetic Services Laboratory, University of Chicago	RCV000223102	SCV002065872	pathogenic	not provided	2021-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166773	SCV002537415	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000197766	SCV002581853	pathogenic	Familial cancer of breast	2022-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509269	SCV002819273	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.277delT (p.Trp93GlyfsX17) 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 was absent in 251224 control chromosomes. c.277delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Lhota_2016, Kleiblova_2019, Lu_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another (likely) pathogenic variant was reported in one of these patients (CHEK2 c.444+1G>A, p.E149fs*6), although other patients with similar diagnoses did not have such co-occurrences (Kleiblova_2019). One publication reports experimental evidence evaluating an impact on protein function, showing a large reduction in phosphorylating activity on the target Kap1 (Boonen_2022). 11 laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000197766	SCV004020130	pathogenic	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000223102	SCV004026325	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	PS4_MOD, PVS1, PM2_SUP
Baylor Genetics	RCV000197766	SCV004217616	pathogenic	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535762	SCV001749901	not provided	CHEK2-Related Cancer Susceptibility		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-17-2020 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.