Submissions for variant NM_007194.4(CHEK2):c.478del (p.Tyr159_Ile160insTer)

dbSNP: rs1225437533

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561136	SCV000676007	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-27	criteria provided, single submitter	clinical testing	The c.478delA pathogenic mutation, located in coding exon 3 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 478. This changes the amino acid at codon 160 from a isoleucine to a stop codon within coding exon 3 (p.I160*). 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.
Invitae	RCV000700987	SCV000829767	pathogenic	Familial cancer of breast	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile160*) 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 variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 486838). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000561136	SCV001733763	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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.
Myriad Genetics, Inc.	RCV000700987	SCV004045262	pathogenic	Familial cancer of breast	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357481	SCV001552964	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The CHEK2 p.Ile160* variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, or Zhejiang University Database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.478del variant leads to a premature stop codon at position 160 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.