Submissions for variant NM_007194.4(CHEK2):c.247del (p.Gln83fs)

dbSNP: rs587782766

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132293	SCV000187378	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The c.247delC pathogenic mutation, located in coding exon 1 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 247, causing a translational frameshift with a predicted alternate stop codon (p.Q83Kfs*27). This mutation was reported in an individual with breast cancer at age 37 and again at age 49 (Kwong A et al. J Mol Diagn, 2020 04;22:544-554). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000204969	SCV000260987	pathogenic	Familial cancer of breast	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln83Lysfs*27) 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 (rs587782766, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 27751358). ClinVar contains an entry for this variant (Variation ID: 142851). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000220709	SCV000279296	pathogenic	not provided	2023-06-13	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); This variant is associated with the following publications: (PMID: 28152038, 28783718, 27751358, 31447099, 29922827, 32805687, 24713400, 21876083, 32068069, 33471991)
Counsyl	RCV000204969	SCV000488749	likely pathogenic	Familial cancer of breast	2016-06-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132293	SCV001736164	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-02	criteria provided, single submitter	clinical testing	This variant deletes 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. This variant has been reported in individuals affected with breast cancer (PMID: 27751358). This variant has been identified in 5/282814 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149913	SCV003838129	likely pathogenic	Breast and/or ovarian cancer	2022-02-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204969	SCV004020139	pathogenic	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000204969	SCV004217562	pathogenic	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987373	SCV004803409	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.247delC (p.Gln83LysfsX27) 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. The variant allele was found at a frequency of 1.6e-05 in 251454 control chromosomes (gnomAD). c.247delC has been reported in the literature in at-least one individual affected with Hereditary Breast And/or Ovarian Cancer Syndrome (example: Lu_2019). The following publication has been ascertained in the context of this evaluation (PMID: 30128536). ClinVar contains an entry for this variant (Variation ID: 142851). Based on the evidence outlined above, the variant was classified as pathogenic.