Submissions for variant NM_007194.4(CHEK2):c.507del (p.Phe169fs)

dbSNP: rs587780183

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254658	SCV000149931	pathogenic	not provided	2023-03-14	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 (Manoukian 2011); Published functional studies demonstrate a damaging effect: absent protein expression and impaired kinase activity (Manoukian et al., 2011; Boonen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast or colorectal cancer (Manoukian et al., 2011; Mork et al., 2019); This variant is associated with the following publications: (PMID: 26681312, 28452373, 21562711, 28152038, 31101557, 32805687, 29922827, 34903604)
Ambry Genetics	RCV000116022	SCV000184398	pathogenic	Hereditary cancer-predisposing syndrome	2013-09-16	criteria provided, single submitter	clinical testing	​The c.507delT pathogenic mutation, located in coding exon 3 of the CHEK2 gene, results from a deletion of one nucleotide at position 507, causing a translational frameshift with a predicted alternate stop codon. This alteration was first reported in an Italian kindred significant for multiple early-onset breast cancers, osteosarcoma, and other neoplasms (Manoukian S et al. Breast Cancer Res Treat. 2011 Nov;130(1):207-15). Of note, no detectable mutation in the BRCA1, BRCA2, or TP53 gene was identified in this family. In addition to the clinical data presented in the literature, and since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV000550157	SCV000633194	pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe169Leufs*2) 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 (rs587780183, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with sarcoma, breast, bladder, and endometrial cancer (PMID: 21562711, 26681312). ClinVar contains an entry for this variant (Variation ID: 128079). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000116022	SCV000905463	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, endometrial cancer and bladder cancer (PMID: 21562711, 26681312, 29522266, 33925588). This variant has been identified in 1/251420 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000254658	SCV002009493	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288601	SCV002579088	pathogenic	Colorectal cancer	2022-07-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000550157	SCV004045078	pathogenic	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000550157	SCV004217545	pathogenic	Familial cancer of breast	2023-09-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254658	SCV004221746	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	The CHEK2 c.507del (p.Phe169Leufs*2) 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 (PMIDs: 26681312 (2015), 21562711 (2011)). The frequency of this variant in the general population, 0.000004 (1/251420 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.