Submissions for variant NM_000051.4(ATM):c.2838+4A>G

gnomAD frequency: 0.00001  dbSNP: rs876659907

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222111	SCV000276849	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The c.2838+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 17 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000222111	SCV000687421	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779800	SCV000916604	uncertain significance	not specified	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2838+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site; while two predict the variant abolishes this 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246006 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2838+4A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215325	SCV001387063	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 18 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 232661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 18 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
PreventionGenetics, part of Exact Sciences	RCV004547551	SCV004119765	uncertain significance	ATM-related disorder	2022-10-26	criteria provided, single submitter	clinical testing	The ATM c.2838+4A>G variant is predicted to interfere with splicing. This variant is predicted to disrupt splicing at a consensus splice site based on splicing prediction programs (Alamut Visual Plus v.1.6.1). However, these prediction programs are not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108139340-A-G) and has been interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232661). Of note, other variants impacting the c.2838 consensus splice site (c.2838G>T, c.2838+1G>A, and c.2838+6T>C) have been documented in patients with breast cancer (Patient MK1C in Table S1, Hamameh et al. 2017. PubMed ID: 28486781), ataxia telangiectasia (referred to as IVS18+1G>A in Buzin et al. 2003. PubMed ID: 12552559), and dystonia (Patient IS-DYS-094 in Suppl. Table 2, Zech et al. 2020. PubMed ID: 33098801), respectively. At this time, the clinical significance of the c.2838+4A>G variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003462502	SCV004205756	uncertain significance	Familial cancer of breast	2023-10-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001215325	SCV002076448	uncertain significance	Ataxia-telangiectasia syndrome	2021-01-26	no assertion criteria provided	clinical testing