Submissions for variant NM_007194.4(CHEK2):c.85C>T (p.Gln29Ter)

gnomAD frequency: 0.00001  dbSNP: rs761494650

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167444	SCV000218300	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	clinical testing	The p.Q29* pathogenic mutation (also known as c.85C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 85. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been identified in a patient with male breast cancer and in an individual with ovarian cancer (Pritzlaff M et al. Breast Cancer Res Treat. 2016 02;161(3):575-586; Harter P et al. PLoS One 2017 Oct;12(10):e0186043). 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	RCV000228262	SCV000289713	pathogenic	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln29*) 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 (rs761494650, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28008555). ClinVar contains an entry for this variant (Variation ID: 187694). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000167444	SCV000292166	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-02	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 28008555, 33919281) and in an individual with prostate cancer (PMID: 28873162). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases, 0/53461 unaffected controls (PMID: 33471991;Leiden Open Variation Database DB-ID CHEK2_000237). This variant has also been identified in 2/249444 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.
GeneDx	RCV000485654	SCV000568938	likely pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.85C>T at the cDNA level and p.Gln29Ter (Q29X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with prostate cancer (Mandelker 2017). It is considered likely pathogenic.
Counsyl	RCV000228262	SCV000677821	likely pathogenic	Familial cancer of breast	2016-12-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485654	SCV001245720	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000228262	SCV001499650	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000228262	SCV002762810	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV000228262	SCV004020143	pathogenic	Familial cancer of breast	2023-03-08	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	RCV000228262	SCV004217553	pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing