Submissions for variant NM_000051.4(ATM):c.496+3A>G

gnomAD frequency: 0.00001  dbSNP: rs876658311

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222498	SCV000273363	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-23	criteria provided, single submitter	clinical testing	The c.496+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 4 in the ATM gene. This nucleotide position is well 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546346	SCV000622548	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 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 likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 229974). 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 5, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 5 have been determined to be pathogenic (PMID: 15054841; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. 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	RCV000222498	SCV000682233	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 5 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/282724 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420751	SCV001623095	uncertain significance	not specified	2021-04-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.496+3A>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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251310 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.496+3A>G has been reported in the literature in at-least one unaffected control individual tested as part of the Carolina breast cancer study (Walsh_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000509292	SCV001993549	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33479248, 35451682)
Baylor Genetics	RCV003468991	SCV004210066	uncertain significance	Familial cancer of breast	2023-08-07	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000509292	SCV000607231	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network	RCV001535556	SCV001749533	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-29-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.