Submissions for variant NM_000051.4(ATM):c.6347+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1057517120

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409839	SCV000486777	likely pathogenic	Ataxia-telangiectasia syndrome	2016-08-04	criteria provided, single submitter	clinical testing
Invitae	RCV000409839	SCV000818964	pathogenic	Ataxia-telangiectasia syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 43 of the ATM 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 (no rsID available, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 10330348). This variant is also known as IVS45+1G>A. ClinVar contains an entry for this variant (Variation ID: 371243). Studies have shown that disruption of this splice site results in skipping of exons 43-45 or intron retention and introduces a premature termination codon (PMID: 10330348; 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	RCV001180642	SCV001345609	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 43 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant leads to the production of multiple abnormal RNA transcripts (PMID: 10330348). Cells derived from the homozygous carrier have shown no detectable ATM protein (PMID: 10330348). This variant has been reported in the homozygous state in an individual affected with ataxia telangiectasia (PMID: 10330348). This variant has been identified in 1/28684 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 Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409839	SCV001623206	pathogenic	Ataxia-telangiectasia syndrome	2021-04-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6347+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and resulted in the production of multiple incorrectly spliced transcripts identified in cDNA (Teraoka_1999). The variant allele was found at a frequency of 5.5e-05 in 36660 control chromosomes (gnomAD and publication data). c.6347+1G>A has been reported in the literature in one homozygous individual affected with Ataxia-Telangiectasia (Teraoka_1999). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000409839	SCV002073082	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The splice donor variant c.6347+1G>A in ATM (NM_000051.4) has been reported previously in an affected patient (Teraoka SN et al). It has been reported to ClinVar as Pathogenic/Likely Pathogenic. The c.6347+1G>A variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucleotide and hence is predicted to cause protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001180642	SCV002657956	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-14	criteria provided, single submitter	clinical testing	The c.6347+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 42 of the ATM gene. This alteration has been identified in the homozygous state in an individual diagnosed with ataxia-telangiectasia (AT) and was reported to cause abnormal splicing (Teraoka SN et al. Am J Hum Genet, 1999 Jun;64:1617-31). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.