Submissions for variant NM_000051.4(ATM):c.9086_9096del (p.Gly3029fs)

dbSNP: rs2137919004

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001939624	SCV002228781	pathogenic	Ataxia-telangiectasia syndrome	2022-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATM protein in which other variant(s) (p.Phe3049Profs*13) have been determined to be pathogenic (PMID: 10817650, 16603769, 19781682). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ATM gene (p.Gly3029Glufs*30). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the ATM protein and extend the protein by 1 additional amino acid residues.
Ambry Genetics	RCV002442947	SCV002682830	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The c.9086_9096del11 pathogenic mutation, located in coding exon 62 of the ATM gene, results from a deletion of 11 nucleotides at nucleotide positions 9086 to 9096, causing a translational frameshift with a predicted alternate stop codon (p.G3029Efs*30). This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 28 amino acids. However, premature stop codons are typically deleterious in nature and this mutation alters the sequence of the FATC domain of the ATM protein which has been shown to be necessary for ATM regulation (Jiang XJ et al. Biol. Chem. 2006 Jun;281(23):15741-6). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with ATM-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004044368	SCV004932500	likely pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16266405, 25614872, 15039971, 21965147].