Submissions for variant NM_000051.4(ATM):c.3994-2A>G

gnomAD frequency: 0.00002  dbSNP: rs587782276

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131133	SCV000186065	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The c.3994-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 26 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198837	SCV000253669	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 26 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 is present in population databases (rs587782276, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with a personal or family history of breast cancer and/or pancreatic cancer (PMID: 24763289, 28956312, 29922827). ClinVar contains an entry for this variant (Variation ID: 142167). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131133	SCV000904688	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 26 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 28956312). This variant has also been identified in 4/248114 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.
GeneDx	RCV001580458	SCV001817496	likely pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies suggest this variant results in a deletion of exon 27 caused by the introduction of a premature termination codon (Bueno-Martinez et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24763289, 28152038, 28956312, 25614872, 23807571, 35022142, 28888541, 35716007, 29922827)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001580458	SCV004027220	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003155922	SCV004203827	pathogenic	Familial cancer of breast	2023-10-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003155922	SCV004932092	likely pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001580458	SCV005199609	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV003155922	SCV002588855	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing