Submissions for variant NM_000051.4(ATM):c.8942del (p.His2981fs)

dbSNP: rs786203489

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166811	SCV000217625	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The c.8942delA pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 8942, causing a translational frameshift with a predicted alternate stop codon (p.H2981Pfs*4). This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 76 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549516	SCV000622866	pathogenic	Ataxia-telangiectasia syndrome	2023-05-23	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.Arg2993*, p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 12815592, 16238588, 18560558, 20840352, 23774824, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 187121). 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 creates a premature translational stop signal (p.His2981Profs*4) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the ATM protein.
Baylor Genetics	RCV003474881	SCV004203805	likely pathogenic	Familial cancer of breast	2023-10-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003474881	SCV004930660	pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.