Submissions for variant NM_007194.4(CHEK2):c.606del (p.Phe202fs)

dbSNP: rs886039609

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254973	SCV000322515	likely pathogenic	not provided	2015-12-18	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in CHEK2 is denoted c.606delT at the cDNA level and p.Phe202LeufsX3 (F202LfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is CTTTTT[T]GATC. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 202, and creates a premature stop codon at position 3 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000775229	SCV000909481	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-02	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 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	RCV001384514	SCV001584026	pathogenic	Familial cancer of breast	2021-07-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265538). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe202Leufs*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).
Ambry Genetics	RCV000775229	SCV002657711	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	The c.606delT pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 606, causing a translational frameshift with a predicted alternate stop codon (p.F202Lfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV001384514	SCV004044421	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.