Submissions for variant NM_007194.4(CHEK2):c.592+3A>T

gnomAD frequency: 0.00001  dbSNP: rs587782849

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132447	SCV000187541	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The c.592+3A>T intronic variant results from an A to T substitution 3 nucleotides after coding exon 3 in the CHEK2 gene. This alteration has been detected in multiple breast cancer cohorts (Hauke J et al. Cancer Med, 2018 04;7:1349-1358;Fostira F et al. J. Med. Genet., 2020 01;57:53-61; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Apostolou P et al. Cancers (Basel), 2021 Apr;13). This alteration was also identified in one patient with colorectal cancer at 39 years of age (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). RNA analysis from a breast cancer patient who carried this variant identified two abnormally spliced transcripts predicted to result nonsense-mediated decay (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102), and another RNA study demonstrated this alteration has a deleterious splicing impact (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, internal RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000656830	SCV000210967	likely pathogenic	not provided	2023-12-08	criteria provided, single submitter	clinical testing	Observed in individuals with CHEK2-related cancers and suggested to be a Greek founder variant (PMID: 27616075, 27978560, 29522266, 32658311, 33925588, 35418818, 35264596); Non-canonical splice site variant demonstrated to result in aberrant splicing leading to a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 27616075, 31843900, 33925588); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.721+3A>T; This variant is associated with the following publications: (PMID: 27616075, 27978560, 29522266, 32658311, 31843900, 31300551, 34426522, 33925588, 35220195, 35264596, 35418818)
Invitae	RCV000228472	SCV000289693	likely pathogenic	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587782849, gnomAD 0.005%). This variant has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 27616075, 27978560, 29522266, 32658311, 33919281, 33980423). ClinVar contains an entry for this variant (Variation ID: 142956). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in complex altered splicing including up regulation of naturally occurring isoforms and skipping of exon 4 (also known as exon 3) and skipping of exon 4 and 5, which introduce premature termination codons. The resulting mRNA is expected to undergo nonsense-mediated decay. This variant causes significant reduction of the normal transcript (PMID: 27616075, 31843900, 33925588; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132447	SCV000537545	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This variant causes an A>T nucleotide substitution at the +3 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies with heterozygous carriers have shown that this variant causes aberrant splicing and causes out-of-frame skipping of exon 4, or exons 4 and 5 (PMID: 27616075, 31843900, 33925588). The observed exon skipping is expected to result in nonsense-mediated decay of the mutant transcripts. An external laboratory has also reported observation of abnormal splicing in multiple carriers based on their internal RNA studies (ClinVar SCV000187541.6). This variant has been reported in over twenty individuals affected with breast cancer (PMID: 27616075, 28486781, 29522266, 31300551, 32658311, 33919281, 33925588, 33980423), colorectal cancer (PMID: 27978560), and prostate cancer (PMID: 35350808). A haplotype analysis has shown a founder effect of this variant for individuals of Greek descent (PMID: 33925588). This variant has also been identified in 8/251318 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656830	SCV000601175	likely pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	The CHEK2 c.592+3A>T variant has been reported in the published literature in in individuals with breast cancer including early age of onset (PMID: 27616075 (2016), 29522266 (2018), 33925588 (2021), 33919281 (2021), 31300551 (2020)) and colorectal cancer (PMID: 27978560 (2016)). This variant was reported to result in aberrant splicing and the alternative transcripts are predicted to result in truncated CHEK2 protein (PMID: 27616075 (2016), 33925588 (2021)). However, another study analyzing the fraction of transcripts in a patient carrying this variant found that 55% of transcripts were wild type (31843900 (2019)). Hence the effects of this splicing on CHECK2 protein function are inconclusive. The frequency of this variant in the general population, 0.034 (297/8700 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV004551270	SCV000746463	likely pathogenic	Malignant tumor of breast	2024-05-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000228472	SCV000839484	pathogenic	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468934	SCV001360505	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-08	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.592+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5 prime splicing donor site, while two predict the variant weakens the 5 prime donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to the skipping of exon 4 and exon 4/5, both predicted to cause a frameshift (e.g. Kraus_2016, Casadei_2019). The variant allele was found at a frequency of 3.6e-05 in 252298 control chromosomes (gnomAD and Akcay_2021). c.592+3A>T has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer, some of these cases were diagnosed at an early age and/or indicated to have a positive family history and several patients were comprehensively genotyped on large cancer gene panels (e.g. Kraus_2016, Lolas Hamameh_2017, Hauke_2018, Fostria_2020, Akcay_2021, Toss_2021, Bora_2022). These reports indicate that the variant is likely associated with Hereditary Breast and Ovarian Cancer, however it should be considered that familial co-segregation data has, to our knowledge, yet to be reported. BLAT searches for the intronic sequence surrounding the variant (30 nucleotide sequence surrounding the location of the variant) gave only 1 hit with 100% sequence identity on chromosome 22 (i.e. at the expected location). Therefore, the variant is unlikely to be derived from a CHEK2 pseudogene. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Eight classified the variant as likely pathogenic (n=7)/pathogenic (n=1), and six classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000656830	SCV001446500	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132447	SCV002537620	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-11	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000228472	SCV002581473	likely pathogenic	Familial cancer of breast	2022-05-18	criteria provided, single submitter	clinical testing
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV000228472	SCV003919095	pathogenic	Familial cancer of breast		criteria provided, single submitter	clinical testing
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV003334383	SCV003919096	pathogenic	Malignant tumor of prostate		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228472	SCV004020108	likely pathogenic	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad Internal Data].
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000656830	SCV004022313	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1
CeGaT Center for Human Genetics Tuebingen	RCV000656830	SCV004033931	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CHEK2: PM2, PS4:Moderate, PP3, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV004532583	SCV004118387	likely pathogenic	CHEK2-related disorder	2024-02-14	criteria provided, single submitter	clinical testing	The CHEK2 c.592+3A>T variant is predicted to interfere with splicing. This variant has been reported in individuals with colorectal cancer (Pearlman et al. 2017, eTable 2. PubMed ID: 27978560; Akcay. 2020. PubMed ID: 32658311; Ercoskun and Ozkan. 2022. PubMed ID: 35418818), breast cancer (Table 1, Kraus et al. 2017. PubMed ID: 27616075; reported as c.721+3A>T in Table 3, Bora et al. 2022. PubMed ID: 35220195; Toss et al. 2021. PubMed ID: 33919281; Ece Solmaz et al. 2021. PubMed ID: 33980423), and breast/ovarian cancer (Table S1, Kauke et al. 2018. PubMed ID:29522266). Functional analysis (RT-PCR) has demonstrated the formation of two different shortened CHEK2 transcripts, one lacking exon 4 and the other lacking exons 4-5 (Figure 1, Kraus et al. 2017. PubMed ID: 27616075). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/142956/). In summary, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000228472	SCV004217481	likely pathogenic	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656830	SCV004225582	likely pathogenic	not provided	2024-05-22	criteria provided, single submitter	clinical testing	PVS1_strong+PS4_mod+PM2_sup
Revvity Omics, Revvity	RCV000656830	SCV004238533	likely pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000228472	SCV000488829	uncertain significance	Familial cancer of breast	2016-06-27	flagged submission	clinical testing
King Laboratory, University of Washington	RCV001171462	SCV001251373	pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2	2019-09-01	no assertion criteria provided	research
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554293	SCV001775480	uncertain significance	Breast carcinoma	2021-08-09	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656830	SCV001978488	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656830	SCV001980144	likely pathogenic	not provided		no assertion criteria provided	clinical testing