Submissions for variant NM_007194.4(CHEK2):c.1542+3A>G

dbSNP: rs1060502722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472776	SCV000550560	uncertain significance	Familial cancer of breast	2022-10-26	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 410067). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. It affects a nucleotide within the consensus splice site.
Ambry Genetics	RCV000568643	SCV000669235	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The c.1542+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 13 in the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested leading to a predicted shift in reading frame (Ambry internal data). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the C- terminus of CHEK2, and is not expected to trigger nonsense-mediated mRNA decay. However, the frameshifted amino acids are predicted to disrupt the nuclear localization signal of the protein (Zannini L et al. J Biol Chem. 2003 Oct 24;278(43):42346-51). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587215	SCV000698781	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: c.1542+3A>G in CHEK2 gene is an intronic change that involves a mildly conserved nucleotide. 3/5 programs in Alamut predict that this variant will affect the normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is absent from the control population datasets of ExAC and gnomAD and has not, to our knowledge, been reported in affected individuals in published reports or cited by reputable databases/clinical laboratories. Considering all, the variant was classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000568643	SCV001340910	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +3 position of intron 14 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant may result in an absent or disrupted protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
GeneDx	RCV000587215	SCV004168905	likely pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	In silico analysis suggests this variant may impact gene splicing; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV000472776	SCV004217541	uncertain significance	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing