Submissions for variant NM_007194.4(CHEK2):c.661_664dup (p.Met222fs)

gnomAD frequency: 0.00002  dbSNP: rs750616657

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164995	SCV000215689	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-04	criteria provided, single submitter	clinical testing	The c.661_664dupATCA pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a duplication of ATCA at nucleotide position 661, causing a translational frameshift with a predicted alternate stop codon (p.M222Nfs*24). One study detected this mutation in 0/3030 pancreatic cancer cases and 4/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). 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.
Color Diagnostics, LLC DBA Color Health	RCV000164995	SCV001351708	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-22	criteria provided, single submitter	clinical testing	This variant inserts 4 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. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/227996 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201228	SCV001372320	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.661_664dupATCA (p.Met222AsnfsX24) 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. The variant allele was found at a frequency of 1.8e-05 in 227996 control chromosomes. c.661_664dupATCA has been reported in the literature in an individual affected with Breast Cancer (Gomez-Flores-Ramos_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29922827, 35406420). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215060	SCV001386780	pathogenic	Familial cancer of breast	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met222Asnfs*24) 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 (rs750616657, gnomAD 0.01%). 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: 185552). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001215060	SCV004044145	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	RCV001215060	SCV004217760	likely pathogenic	Familial cancer of breast	2021-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477612	SCV004221752	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. The variant has not been reported in individuals with CHEK2-related diseases in the published literature. The frequency of this variant in the general population, 0.000126 (4/31670 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.