Submissions for variant NM_000051.4(ATM):c.1442T>G (p.Leu481Ter)

gnomAD frequency: 0.00001  dbSNP: rs1555070980

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221550	SCV002499303	pathogenic	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.1442T>G (p.Leu481Ter) variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID 21665257: PM3_Strong). This variant is absent in GnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Invitae	RCV000546281	SCV000622258	pathogenic	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu481*) 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: 21665257). ClinVar contains an entry for this variant (Variation ID: 453367). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000564972	SCV000660481	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	The p.L481* pathogenic mutation (also known as c.1442T>G), located in coding exon 9 of the ATM gene, results from a T to G substitution at nucleotide position 1442. This changes the amino acid from a leucine to a stop codon within coding exon 9. In one study, an individual with ataxia-telangiectasia (A-T) was found to be compound heterozygous for this mutation and another frameshift alteration in ATM (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This mutation has also been reported in an individual with metastatic prostate cancer (Castro E et al. J Clin Oncol, 2019 02;37:490-503). 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.
Counsyl	RCV000546281	SCV000678176	likely pathogenic	Ataxia-telangiectasia syndrome	2017-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000657713	SCV000779462	pathogenic	not provided	2022-06-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21665257, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000762814	SCV000893172	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564972	SCV000910321	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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 compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 21665257). This variant has also been reported in individuals affected with metastatic prostate cancer (PMID: 30625039) or renal cell carcinoma (PMID: 35441217). 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	RCV002221550	SCV004212059	pathogenic	Familial cancer of breast	2023-03-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221550	SCV004931338	pathogenic	Familial cancer of breast	2024-01-16	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.