Submissions for variant NM_000051.4(ATM):c.4507C>T (p.Gln1503Ter)

gnomAD frequency: 0.00004  dbSNP: rs1131691164

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000493310	SCV000581470	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-04	criteria provided, single submitter	clinical testing	The p.Q1503* pathogenic mutation (also known as c.4507C>T), located in coding exon 29 of the ATM gene, results from a C to T substitution at nucleotide position 4507. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This alteration has been well described in multiple Ataxia-Telangiectasia families and has been reported as a founder mutation in the Costa Rican population (Mitui M et al, Hum. Mutat. 2003 Jul; 22(1):43-50; Telatar M et al, Mol. Genet. Metab. 1998 May; 64(1):36-4; Termsarasab P et al, Tremor Other Hyperkinet Mov (N Y) 2015 ; 5:298). This alteration was also identified in a female diagnosed with breast cancer (Llach J et al. Cancers (Basel), 2020 Aug;12:). 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	RCV000545871	SCV000622508	pathogenic	Ataxia-telangiectasia syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1503*) 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 present in population databases (no rsID available, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9682216). ClinVar contains an entry for this variant (Variation ID: 429084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657609	SCV000779351	likely pathogenic	not provided	2017-03-31	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4507C>T at the cDNA level and p.Gln1503Ter (Q1503X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>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, in both the homozygous and compound heterozygous state, in at least two individuals with ataxia telengiectasia and has been reported as a Costa Rican founder variant (Rivero-Carmena 2000). We consider this variant to be a likely pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV000762822	SCV000893180	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000545871	SCV002020676	pathogenic	Ataxia-telangiectasia syndrome	2019-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470610	SCV004210203	pathogenic	Familial cancer of breast	2023-07-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470610	SCV004930397	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.