Submissions for variant NM_007194.4(CHEK2):c.279G>A (p.Trp93Ter)

gnomAD frequency: 0.00002  dbSNP: rs587782070

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130559	SCV000185430	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-04	criteria provided, single submitter	clinical testing	The p.W93* pathogenic mutation (also known as c.279G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 279. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). 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.
Invitae	RCV000199638	SCV000253901	pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp93*) 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 (rs587782070, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 27751358, 28779002). ClinVar contains an entry for this variant (Variation ID: 141866). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000377793	SCV000329277	pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Nonsense 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: 29922827, 28152038, 32805687, 27751358, 28779002, 33257031, 29625052, 33471991, 34204722, 34072659, 32906215, 30128536, 33479248, 36232851)
Color Diagnostics, LLC DBA Color Health	RCV000130559	SCV000911685	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a 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 with breast cancer (PMID: 28779002, 33479248, 34204722). This variant has been identified in 6/251270 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001267682	SCV001445922	pathogenic	Breast and colorectal cancer, susceptibility to	2019-08-30	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 2 of 16 is predicted to result in loss of normal protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/246188) and thus is presumed to be rare. This variant has been reported as Pathogenic by multiple clinical diagnostic laboratories in the ClinVar database (Variation ID: 141866). This variant has been reported in individuals undergoing multi-gene panel testing for breast cancer risk (PMID: 27751358) and was identified in a large cohort study of individuals with breast cancer (PMID: 28779002). The c.279G>A (p.Trp93Ter) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.279G>A (p.Trp93Ter) variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228315	SCV002511767	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.279G>A (p.Trp93X) 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 allele was found at a frequency of 2.4e-05 in 251270 control chromosomes. c.279G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer and other tumor phenotypes (e.g. Vargas-Parra_2020, Walsh_2021, Fonfria_2021, Solano_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000130559	SCV002537416	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000199638	SCV004044279	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.
Baylor Genetics	RCV000199638	SCV004217701	pathogenic	Familial cancer of breast	2023-02-03	criteria provided, single submitter	clinical testing