Submissions for variant NM_007194.4(CHEK2):c.817_818del (p.Glu273fs)

dbSNP: rs1474786480

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582032	SCV000689729	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 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. This variant has been identified in 1/250118 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.
Invitae	RCV000802961	SCV000942812	pathogenic	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu273Asnfs*16) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 491643). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000582032	SCV002680058	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-19	criteria provided, single submitter	clinical testing	The c.817_818delGA pathogenic mutation, located in coding exon 6 of the CHEK2 gene, results from a deletion of two nucleotides at nucleotide positions 817 to 818, causing a translational frameshift with a predicted alternate stop codon (p.E273Nfs*16). This alteration was identified in 1/2000 Australian breast or ovarian cancer patients and not detected in 1997 controls undergoing multigene panel testing for hereditary cancer risk (Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV000802961	SCV004044142	pathogenic	Familial cancer of breast	2023-06-27	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	RCV000802961	SCV004217711	pathogenic	Familial cancer of breast	2023-01-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355310	SCV001550165	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Glu273AsnfsX16 variant was identified in 1 of 4000 proband chromosomes (frequency: 0.0003) from individuals or families with BRCA1/2 negative breast cancer and a strong family history and, it was not identified in 3996 control chromosomes from cancer free individuals (Thompson_2016_26786923). The variant was not identified in the following databases: dbSNP, ClinVar, Clinvitae, Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.817_818delGA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 273 and leads to a premature stop codon 16 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 in hereditary breast cancer 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.