Submissions for variant NM_007194.4(CHEK2):c.616_617del (p.Val206fs)

dbSNP: rs1346554630

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540422	SCV000633202	pathogenic	Familial cancer of breast	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val206Argfs*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 (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 460846). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000564621	SCV000661701	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	clinical testing	The c.616_617delGT pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a deletion of two nucleotides at nucleotide positions 616 to 617, causing a translational frameshift with a predicted alternate stop codon (p.V206Rfs*2). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564621	SCV000689707	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 5 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/224186 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.
GeneDx	RCV000657297	SCV000779028	pathogenic	not provided	2025-02-19	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30927677, 29922827, 32805687)
Mendelics	RCV000540422	SCV001141361	pathogenic	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002217	SCV001160091	pathogenic	not specified	2018-11-13	criteria provided, single submitter	clinical testing	The CHEK2 c.616_617delGT; p.Val206fs variant (rs1346554630), to our knowledge, is not reported in the medical literature but is reported as pathogenic in ClinVar (Variation ID: 460846). This variant is found in the general population with a low overall allele frequency of 0.0004% (1/261372 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657297	SCV002774276	likely pathogenic	not provided	2021-09-02	criteria provided, single submitter	clinical testing	This frameshift variant is predicted to cause the premature termination of CHEK2 protein synthesis. To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000540422	SCV004043809	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	RCV000540422	SCV004217707	likely pathogenic	Familial cancer of breast	2023-11-27	criteria provided, single submitter	clinical testing