Submissions for variant NM_007194.4(CHEK2):c.444+3A>G

gnomAD frequency: 0.00001  dbSNP: rs587781279

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128944	SCV000172819	likely benign	Hereditary cancer-predisposing syndrome	2019-09-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000231163	SCV000289688	likely benign	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000231163	SCV000488832	uncertain significance	Familial cancer of breast	2016-06-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000578769	SCV000680662	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 18058223, 32957588, 33840814)
Color Diagnostics, LLC DBA Color Health	RCV000128944	SCV000689687	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +3 position of intron 3 of the CHEK2 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. A minigene assay showed this variant predominantly expressed the full-length transcript (PMID: 37725924). This variant has been reported in an individual with personal or family history of breast, ovarian or pancreatic cancer (PMID: 32957588). This variant has been reported in a child affected with osteosarcoma and in her mother affected with breast cancer (PMID: 33840814). This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	RCV000128944	SCV001482295	uncertain significance	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000231163	SCV004020231	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355288	SCV001550128	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 c.444+3A>G variant was not identified in the literature nor was it identified in Cosmic, or the Zhejiang University database. The variant was identified in dbSNP (ID: rs587781279) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx and Color Genomics). The variant was identified in control databases in 2 of 246042 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 2 of 111510 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.444+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.