Submissions for variant NM_000051.4(ATM):c.4318A>T (p.Lys1440Ter)

dbSNP: rs1060501551

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464318	SCV000546697	pathogenic	Ataxia-telangiectasia syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1440*) 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 premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 9711876). ClinVar contains an entry for this variant (Variation ID: 407482). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657607	SCV000779349	pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4318A>T at the cDNA level and p.Lys1440Ter (K1440X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous state in an individual with ataxia telangiectasia (Sasaki 1998). We consider ATM Lys1440Ter to be pathogenic.
Counsyl	RCV000464318	SCV000793974	likely pathogenic	Ataxia-telangiectasia syndrome	2017-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022283	SCV001183998	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-21	criteria provided, single submitter	clinical testing	The p.K1440* pathogenic mutation (also known as c.4318A>T), located in coding exon 28 of the ATM gene, results from an A to T substitution at nucleotide position 4318. This changes the amino acid from a lysine to a stop codon within coding exon 28. This alteration was identified in the homozygous state in an individual diagnosed with ataxia telangiectasia (Sasaki T et al. Hum. Mutat. 1998;12:186-95). 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.
Color Diagnostics, LLC DBA Color Health	RCV001022283	SCV001351778	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 29 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 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.
Sema4, Sema4	RCV001022283	SCV002534645	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV004022640	SCV004932154	pathogenic	Familial cancer of breast	2024-01-24	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.