Submissions for variant NM_000051.4(ATM):c.7789-3T>G

dbSNP: rs864622185

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206828	SCV000259612	pathogenic	Ataxia-telangiectasia syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 52 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 8808599, 12815592, 17124347, 21965147). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 219629). 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 skipping of exon 53 (also known as exon 55) and introduces a premature termination codon (PMID: 8808599). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000562166	SCV000665478	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	The c.7789-3T>G intronic variant results from a T to G substitution 3 nucleotides upstream from coding exon 52 in the ATM gene. This alteration has been reported in conjunction with a second ATM alteration in multiple patients with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct; 59(4):839-46; Mitui M et al. Hum. Mutat. 2003 Jul; 22(1):43-50; Coutinho G et al. Am. J. Med. Genet. A 2004 Apr; 126A(1):33-40; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64; Demuth I et al. Neurogenetics 2011 Nov; 12(4):273-82). In one study, this alteration was found to result in alternatively spliced cDNA due to skipping of coding exon 53 (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46). Of note, this alteration is also designated as IVS54-3T>G in published literature. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000562166	SCV000682436	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -3 position of intron 52 of the ATM gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 53 (referred to as exon 55 in the literature) resulting in a frameshift and premature truncation (PMID: 8808599). This variant has been reported in the homozygous state and in the compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 8808599, 12815592, 17124347, 21965147). This variant has also been detected in a cohort of individuals affected with breast cancer (PMID: 35264596). This variant has been identified in 1/249636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000206828	SCV000791081	likely pathogenic	Ataxia-telangiectasia syndrome	2017-04-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000206828	SCV000838597	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310118	SCV001499660	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562166	SCV002538204	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-09	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV003326373	SCV004033162	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATM: PM3:Strong, PM2, PP3
Baylor Genetics	RCV001310118	SCV004216244	pathogenic	Familial cancer of breast	2021-01-28	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001270955	SCV001451759	likely pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing