Submissions for variant NM_000051.4(ATM):c.7788+1G>T

dbSNP: rs1565534524

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684980	SCV000812448	likely pathogenic	Ataxia-telangiectasia syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 52 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant has not been reported in the literature in individuals affected with ATM-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 565420).
Ambry Genetics	RCV003278986	SCV004009295	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The c.7788+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 51 of the ATM gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. As such, this alteration is classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355283	SCV001550119	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM c.7788+1G>T variant was not identified in the literature nor was it identified in the dbSNP or LOVD 3.0 databases. The variant was identified in ClinVar (classified as likely pathogenic by Invitae). The variant was not identified in the following databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.7788+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict the elimination of the 5’ splice site. Exon skipping is a common consequence of a variant that alters splicing at the canonical splice site and exon skipping of exon 52 of the ATM gene would cause an in-frame deletion. Exon 52 is not part of a known functional domain and comprises <5% of the gene and gene product. Therefore it remains unclear whether or not this variant would disrupt the function of the gene. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.