Submissions for variant NM_007194.4(CHEK2):c.58C>T (p.Gln20Ter)

dbSNP: rs536907995

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255024	SCV000322541	likely pathogenic	not provided	2022-02-03	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 a significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history of CHEK2-related cancers in published literature (Foley 2015, Baloch 2016, Scarpa 2017, Sun 2017, Fan 2018, Akcay 2020); This variant is associated with the following publications: (PMID: 26023681, 28724667, 28199314, 27039729, 24728327, 27510020, 29356917, 28779002, 29922827, 28553140, 32658311)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458969	SCV000550527	pathogenic	Familial cancer of breast	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln20*) 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 (rs536907995, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000458969	SCV000677811	pathogenic	Familial cancer of breast	2017-06-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579628	SCV000684663	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-20	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 reported in individuals affected with breast cancer (PMID: 27039729, 28724667, 32658311, 32885271), an individual affected with ovarian cancer (PMID: 32885271) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000005). This variant has also been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic variant in the BRCA2 gene (PMID: 26023681). This variant is found at a high frequency in the South Asian population (0.1145%, 35/30544 chromosomes) by the Genome Aggregation Database (gnomAD), suggesting its penetrance may be reduced relative to other pathogenic CHEK2 alleles. Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic
Ambry Genetics	RCV000579628	SCV001186719	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-18	criteria provided, single submitter	clinical testing	The p.Q20* pathogenic mutation (also known as c.58C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 58. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration was detected in conjunction with a pathogenic BRCA2 mutation in an individual diagnosed with breast cancer at ages 37 and 61 and ovarian cancer at age 56 (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81). This alteration has also been observed in breast cancer cohorts (Baloch AH et al. Asian Pac. J. Cancer Prev. 2016;17:1089-92; Sun J et al. Clin Cancer Res 2017 Oct;23(20):6113-6119). In one case-control study, this alteration was not identified in 13087 breast cancer cases but was seen in 1/5488 control individuals in the United Kingdom; of note, study subjects were under the age of 55 years (Decker B et al. J Med Genet 2017 11;54(11):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.
Revvity Omics, Revvity	RCV000255024	SCV002019290	pathogenic	not provided	2019-03-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000458969	SCV002518704	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579628	SCV002537618	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255024	SCV002774274	likely pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	This nonsense variant is predicted to cause the premature termination of CHEK2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMIDs: 26023681 (2015), 27510020 (2016), 28724667 (2017), 32658311 (2021), and 32885271 (2021)). Based on the available information, this variant is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000458969	SCV004020230	pathogenic	Familial cancer of breast	2023-03-09	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000458969	SCV004034964	pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing	A pathogenic mutation was detected in the CHEK2 gene (c.58C>T).This sequence change creates a premature translational stop signal (p.Gln20*) in the CHEK2 gene. This variant is expected to result in an absent or non-functional protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant Not observed at a significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887) classified as pathogenic with no conflict . For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000458969	SCV004217710	pathogenic	Familial cancer of breast	2023-01-17	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992188	SCV004809421	likely pathogenic	Li-Fraumeni syndrome 2	2024-04-04	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584196	SCV005068341	uncertain significance	Inherited breast cancer and ovarian cancer	2024-04-24	criteria provided, single submitter	clinical testing	PVS1_Moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796025	SCV005416391	pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer		criteria provided, single submitter	clinical testing	PM2+PS4_Supporting+PVS1
ITMI	RCV000120552	SCV000084706	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356492	SCV001551678	pathogenic	Familial ovarian cancer		no assertion criteria provided	clinical testing	The CHEK2 p.Gln20* variant was identified in 2 of 858 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Baloch 2016, Foley 2014). The variant was also identified in dbSNP (ID: rs536907995) as "With Pathogenic allele", and in ClinVar (classified as likely pathogenic by GeneDx, Color Genomics; as pathogenic by Invitae, Counsyl). The variant was not identified in the Zhejiang University database. The variant was identified in control databases in 36 of 242162 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 36 of 30708 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The c.58C>T variant leads to a premature stop codon at position 20 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2-associated cancers and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001640105	SCV001852742	pathogenic	Breast carcinoma	2021-09-12	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000255024	SCV001977700	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255024	SCV001980298	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000255024	SCV002036776	pathogenic	not provided		no assertion criteria provided	clinical testing
Biotechnology, Institute of Science, Nirma University	RCV000458969	SCV004812175	pathogenic	Familial cancer of breast	2023-10-26	no assertion criteria provided	clinical testing	The CHEK2 constitutional genetic variant leads to a premature truncation of the protein at 20 amino acids leading to loss of the domains crucial for the interaction of proteins like ATM/BRCA2 which are master regulator of the DNA damage repair pathways. The outcome of this mutation could be observed in various cancers specially breast and ovarian cancers, which also corroborates with the familial breast cancer history of the proband, although the proband is yet asymptomatic. Hence, keeping in view the functional effect the variant has been classified pathogenic.