Submissions for variant NM_007194.4(CHEK2):c.269dup (p.Ala91fs)

dbSNP: rs1555932231

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574542	SCV000661766	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The c.269dupC pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a duplication of C at nucleotide position 269, causing a translational frameshift with a predicted alternate stop codon (p.A91Cfs*17). 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	RCV000574542	SCV001735581	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 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 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.
Invitae	RCV001858099	SCV002168396	pathogenic	Familial cancer of breast	2021-03-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 479577). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala91Cysfs*17) 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).
Myriad Genetics, Inc.	RCV001858099	SCV004045375	pathogenic	Familial cancer of breast	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.