Submissions for variant NM_007194.4(CHEK2):c.1434del (p.Glu479fs)

dbSNP: rs786202601

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165489	SCV000216220	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	clinical testing	The c.1434delA pathogenic mutation, located in coding exon 12 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1434, causing a translational frameshift with a predicted alternate stop codon (p.E479Kfs*3). 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.
GeneDx	RCV000222773	SCV000279829	pathogenic	not provided	2023-08-14	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32805687, 27751358, 37490054)
Invitae	RCV000458226	SCV000550472	pathogenic	Familial cancer of breast	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu479Lysfs*3) 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: 27751358). ClinVar contains an entry for this variant (Variation ID: 185972). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588604	SCV000698779	pathogenic	Li-Fraumeni syndrome	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1434delA (p.Glu479LysfsX3) 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 233796 control chromosomes (gnomAD). The variant, c.1434delA, has been reported in the literature in two individuals who were referred for multi-gene cancer panel testing, but with limited available information (Leedom_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165489	SCV000911177	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 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 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.
Myriad Genetics, Inc.	RCV000458226	SCV004045004	pathogenic	Familial cancer of breast	2023-06-28	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	RCV000458226	SCV004217654	pathogenic	Familial cancer of breast	2023-06-21	criteria provided, single submitter	clinical testing