Submissions for variant NM_000051.4(ATM):c.378del (p.Asp126fs)

dbSNP: rs587781449

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129372	SCV000184136	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The c.378delT pathogenic mutation, located in coding exon 4 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 378, causing a translational frameshift with a predicted alternate stop codon (p.D126Efs*3). This mutation has been identified in a patient with bilateral breast cancer (Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163:383-390). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000464543	SCV000546723	pathogenic	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp126Glufs*3) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). 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: 141037). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129372	SCV000682160	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV000657371	SCV000779104	pathogenic	not provided	2017-08-11	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in ATM is denoted c.378delT at the cDNA level and p.Asp126GlufsX3 (D126EfsX3) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGGA[delT]ACAG. The deletion causes a frameshift which changes an Aspartic Acid to a Glutamic Acid at codon 126, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.378delT has been observed in a woman with bilateral breast cancer (Crawford 2017). We consider this variant to be pathogenic.
Counsyl	RCV000464543	SCV000790486	likely pathogenic	Ataxia-telangiectasia syndrome	2017-04-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019729	SCV004930557	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.