Submissions for variant NM_000051.4(ATM):c.6040G>T (p.Glu2014Ter)

dbSNP: rs375783941

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412041	SCV000486976	likely pathogenic	Ataxia-telangiectasia syndrome	2016-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000657612	SCV000779354	pathogenic	not provided	2018-03-07	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6040G>T at the cDNA level and p.Glu2014Ter (E2014X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported as homozygous in a patient with Ataxia Telangiectasia (Sandoval 1999), and is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412041	SCV000833459	pathogenic	Ataxia-telangiectasia syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 9887333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu2014*) 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). ClinVar contains an entry for this variant (Variation ID: 371405). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Color Diagnostics, LLC DBA Color Health	RCV000775840	SCV000910311	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 41 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous state in an individual affected with ataxia telangiectasia (PMID: 9887333). 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272219	SCV002556827	likely pathogenic	Familial cancer of breast	2022-03-07	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002272219	SCV002580842	pathogenic	Familial cancer of breast	2022-02-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775840	SCV002658407	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	The p.E2014* variant (also known as c.6040G>T), located in coding exon 40 of the ATM gene, results from a G to T substitution at nucleotide position 6040. This changes the amino acid from a glutamic acid to a stop codon within coding exon 40. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150193	SCV003837847	likely pathogenic	Breast and/or ovarian cancer	2022-02-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002272219	SCV004933070	pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.