Submissions for variant NM_000051.4(ATM):c.3320T>A (p.Leu1107Ter)

dbSNP: rs1060501711

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460640	SCV000547160	pathogenic	Ataxia-telangiectasia syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1107*) 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: 407734). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000485900	SCV000564616	pathogenic	not provided	2014-11-06	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted ATM c.3320T>A at the cDNA level and p.Leu1107Ter (L1107X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Ambry Genetics	RCV000571628	SCV000665185	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	clinical testing	The p.L1107* pathogenic mutation (also known as c.3320T>A), located in coding exon 22 of the ATM gene, results from a T to A substitution at nucleotide position 3320. This changes the amino acid from a leucine to a stop codon within coding exon 22. This variant has been identified in a prostate cancer cohort (Na R et al. Eur Urol, 2017 05;71:740-747). 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	RCV000571628	SCV000910260	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 23 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.
Baylor Genetics	RCV003470445	SCV004209522	pathogenic	Familial cancer of breast	2024-02-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000460640	SCV001457138	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004740236	SCV005344057	pathogenic	ATM-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The ATM c.3320T>A variant is predicted to result in premature protein termination (p.Leu1107*). This variant has been reported in individual(s) with prostate cancer (example, Fig. 1, Na et al 2017. PubMed ID: 27989354). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407734/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.