ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1235+4_1235+5del

dbSNP: rs770033355
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481339 SCV000567832 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1235+4_1235+5delAA or IVS9+4_IVS9+5delAA and consists of a deletion of two nucleotides at the +4 to +5 position in intron 9 of the ATM gene. The normal sequence, with the bases that are deleted in braces, is Ggta[delaa]gtgt, where the capital letter is exonic and the lowercase letters are intronic. This deletion is predicted to destroy the nearby natural splice donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. ATM c.1235+4_1235+5delAA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotides that are deleted are conserved in mammals. Based on the currently available information, it is unclear whether ATM c.1235+4_1235+5delAA is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568923 SCV000665551 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-04 criteria provided, single submitter clinical testing The c.1235+4_1235+5delAA intronic variant, located downstream of coding exon 8 of the ATM gene, results from a deletion of two nucleotides at positions 1235+4 and 1235+5. These nucleotide positions are well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Internal RNA studies showed this variant leads to alternate splicing; however, the alternate transcript was also present in controls (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000805666 SCV000945632 pathogenic Ataxia-telangiectasia syndrome 2023-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 9 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 (rs770033355, gnomAD 0.007%). This variant has been observed in individual(s) with male breast cancer (PMID: 30613976). ClinVar contains an entry for this variant (Variation ID: 419780). 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 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000568923 SCV001347295 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing This variant deletes 2 basepairs in intron 9 of the ATM gene, affecting non-canonical sequence of the splice donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, although this prediction has not been confirmed in published RNA studies. 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 been identified in 1/251026 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 RCV003230515 SCV003929025 uncertain significance not specified 2023-04-20 criteria provided, single submitter clinical testing Variant summary: ATM c.1235+4_1235+5delAA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251026 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1235+4_1235+5delAA has been reported in the literature in a male breast cancer patient without strong evidence of causality (Rizzolo_2019). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV003470547 SCV004210241 likely pathogenic Familial cancer of breast 2023-11-22 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000481339 SCV004230076 uncertain significance not provided 2023-01-12 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded inconclusive predictions regarding the effect of this variant on RNA splicing.
CeGaT Center for Human Genetics Tuebingen RCV000481339 SCV004701910 uncertain significance not provided 2023-12-01 criteria provided, single submitter clinical testing ATM: PM2, PP3
Natera, Inc. RCV000805666 SCV001456886 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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