Submissions for variant NM_007194.4(CHEK2):c.1462-2A>G

dbSNP: rs587782575

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131803	SCV000186856	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-02	criteria provided, single submitter	clinical testing	The c.1462-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 13 in the CHEK2 gene. In one study, this alteration was detected in one patient with breast cancer from a cohort of 11416 patients with breast and/or ovarian cancer and was not detected in 3988 control subjects from the United States (Lu HM et al. JAMA Oncol, 2019 01;5:51-57). In another study, this alteration was not detected in 1434 cases of invasive lobular breast cancer or 368 cases of LCIS but was detected in 1/1611 control individuals from the United Kingdom (Petridis C et al. Cancer Epidemiol. Biomarkers Prev., 2019 Jul;28:1162-1168). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000555386	SCV000633137	pathogenic	Familial cancer of breast	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587782575, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 24763289, 27751358, 30128536). ClinVar contains an entry for this variant (Variation ID: 142596). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131803	SCV000684597	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-10	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 13 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in several individuals affected with breast cancer (PMID: 30128536, Color internal data) and in an unaffected individual from a breast cancer case-control study (PMID: 31263054). This variant has been identified in 1/233334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although functional consequence of this variant has not yet been demonstrated, observation of this rare variant and other c.1462-1G>A variant that impacts the same splice site (ClinVar variation ID: 410026) in individuals affected with CHEK2-related cancers suggest that this variant may be associated with disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Sema4, Sema4	RCV000131803	SCV002537380	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-12-23	criteria provided, single submitter	curation
Baylor Genetics	RCV000555386	SCV004217747	likely pathogenic	Familial cancer of breast	2022-02-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884358	SCV004702198	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CHEK2: PVS1:Strong, PM2, PS4:Supporting