ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7789-3T>G (rs864622185)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206828 SCV000259612 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 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, but it affects a nucleotide within the consensus splice site of the intron. 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 (ExAC no frequency). This variant has been observed as homozygous or on the opposite chromosome (in trans) from other pathogenic variants in several individuals affected with ataxia-telangiectasia (PMID: 8808599, 21965147, 17124347, 12815592). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 219629). Studies have shown that this variant is associated with skipping of exon 53 (also known as exon 55), which introduces a frameshift (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 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-30 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. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000562166 SCV000682436 pathogenic Hereditary cancer-predisposing syndrome 2015-11-30 criteria provided, single submitter clinical testing
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
CZECANCA consortium RCV001270955 SCV001451759 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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