Submissions for variant NM_007194.4(CHEK2):c.1188del (p.Val397fs)

dbSNP: rs753159426

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234460	SCV000289652	pathogenic	Familial cancer of breast	2024-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val397Phefs*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). This variant is present in population databases (rs753159426, gnomAD 0.003%). 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: 240730). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492286	SCV000581180	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-08	criteria provided, single submitter	clinical testing	The c.1188delT pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1188, causing a translational frameshift with a predicted alternate stop codon (p.V397Ffs*17). This mutation was detected in 1/1382 Greek breast cancer patients who underwent multigene panel testing (Fostira F et al. J Med Genet, 2020 01;57:53-61). 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.
Mendelics	RCV000234460	SCV000839464	likely pathogenic	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000492286	SCV000913580	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 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 been observed in individuals affected with familial breast cancer (Color internal data). This variant has been identified in 2/282458 chromosomes 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.	RCV000234460	SCV004044087	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.
GeneDx	RCV004725114	SCV005332346	likely pathogenic	not provided	2023-10-18	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); Observed in individuals with breast cancer (Fostira et al., 2020; Apostolou et al., 2021); This variant is associated with the following publications: (PMID: 31589614, 29922827, 31300551, 33925588)