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

dbSNP: rs770033355

Total submissions: 9

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