Submissions for variant NM_000051.4(ATM):c.7788+3A>G

dbSNP: rs869312788

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482677	SCV000569003	likely pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Intronic variant demonstrated to result in the in-frame skipping of exon 52, which includes the critical FAT domain, as well as out-of-frame exons 52-53, and exon 53 (Stracker et al., 2014; Rofes et al., 2020); Non-canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33011440, 33280026, 23532176, DeStefano2016[Article])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779769	SCV000916558	uncertain significance	not specified	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.7788+3A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict the weakening or loss of a 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 119830 control chromosomes and was reported in one patient with AT along with a truncating ATM mutation and one patient with ovarian cancer in the literature. One clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317104	SCV001507751	likely pathogenic	Ataxia-telangiectasia syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 52 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 been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 33011440; De Stefano et al. 2016. J Lab Med. 40(4): 255–261). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 420257). 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 altered splicing resulting in unknown protein product impact (PMID: 33011440). 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.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV001692142	SCV001911486	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.7788+3A>G variant it is predicted to disrupt the donor splice site for intron 52. The skipping of exon 52 predicted by default would result in an in-frame deletion of 53 codons (r. .7630_7788del, p.Leu2544_Glu2596del, PP3). Splicing studies performed by two independent laboratories with heterozygous carrier RNA from breast cancer patients confirmed the presence of the predicted transcript with a band intensity comparable to that of the wild-type band (r.7630_7927del p.Leu2544Lysfs*3, O. Díez, unpublished and PMID: 33011440). Sanger sequencing also revealed a very minor transcript corresponding to the out-of-frame skipping of exons 52 and 53 (PMID: 33011440). Although the major transcript is in frame, the skipped exon 52 is located in the FAT domain and contains the nucleotides deleted in the pathogenic in-frame deletion pathogenic variant c.7638_7646del. These RNA results and their expected consequence allow for a funtional supporting code (PS3_Supporting). The c.7788+3A>G variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It has been reported in one ataxia-telangiectasia proband in trans with c.5932G > T (p.Glu1978*), which awards it with 1 point as per ClinGen SVI Recommendation for in trans Criterion (PM3, De Stefano, 2016 https://doi.org/10.1515/labmed-2016-0018). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM3 + PP3 + PS3_Supporting (PMID: 33280026).
Ambry Genetics	RCV001692142	SCV002674706	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-06	criteria provided, single submitter	clinical testing	The c.7788+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 51 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 donor site. In a study involving RNA extraction for RT-PCR and Sanger sequencing of 10 hereditary cancer genes, incomplete disruption of the natural splice site was observed for this alteration (Rofes P et al. J Mol Diagn, 2020 12;22:1453-1468). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.