Submissions for variant NM_000051.4(ATM):c.3746+4A>G

dbSNP: rs1555092593

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000842482	SCV000984504	likely benign	not provided	2018-04-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV001021027	SCV001182589	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	The c.3746+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 24 in the ATM gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001021027	SCV001340922	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-30	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +4 position of intron 25 of the ATM gene. Splice site prediction tools (3/4) suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247588	SCV001421018	uncertain significance	Ataxia-telangiectasia syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 25 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 682396). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.