Submissions for variant NM_000051.4(ATM):c.1235+3A>G

gnomAD frequency: 0.00001  dbSNP: rs1417190414

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570921	SCV000667890	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The c.1235+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was identified in conjunction with another ATM alteration (c.6205C>T, p.Gln2069*) in a patient diagnosed with adult-onset, variant ataxia-telangiectasia (Krenn M et al. Neurol Genet. 2019 Aug;5:e346). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698429	SCV000827090	pathogenic	Ataxia-telangiectasia syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 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 present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive ataxia-telangiectasia (PMID: 31403082). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 482570). 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 9 and introduces a premature termination codon (PMID: 31403082; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000698429	SCV001150018	pathogenic	Ataxia-telangiectasia syndrome	2019-02-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570921	SCV002530209	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-26	criteria provided, single submitter	curation
Baylor Genetics	RCV003465220	SCV004212022	uncertain significance	Familial cancer of breast	2023-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570921	SCV004358870	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 9 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has detected the out-of-frame skipping of exon 9 in RNA from a heterozygous carrier (PMID: 31403082), although the completeness of the splicing defect was not determined. This variant has been reported in two siblings affected with adult-onset and mild ataxia telangiectasia with an ATM pathogenic covariant, c.6205C>T (p.Gln2069*) (PMID: 31403082). There is no personal and family history of cancer reported in this case study (PMID: 31403082). This variant has been identified in 2/251020 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV004721451	SCV005327541	likely pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in exon skipping (Krenn et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Observed with a second pathogenic ATM variant (phase unknown) in two siblings with adult-onset ataxia, nystagmus, and dysarthria (Krenn et al., 2019); This variant is associated with the following publications: (PMID: 31403082, Zureick2023[Article])