Submissions for variant NM_000051.4(ATM):c.5573G>A (p.Trp1858Ter)

dbSNP: rs879254076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236378	SCV000293377	pathogenic	not provided	2017-01-16	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted ATM c.5573G>A at the cDNA level and p.Trp1858Ter (W1858X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), 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, the adjacent variant c.5574G>A, which also results in a premature stop codon at this residue (p.Trp1858Ter) has been reported in the compound heterozygous state with another ATM pathogenic variant in an individual with Ataxia-telangiectasia (Delia 2000). We therefore consider ATM c.5573G>A to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628037	SCV000748925	pathogenic	Ataxia-telangiectasia syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1858*) 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: 246068). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000628037	SCV000790919	likely pathogenic	Ataxia-telangiectasia syndrome	2017-04-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000628037	SCV001150022	pathogenic	Ataxia-telangiectasia syndrome	2019-06-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002347925	SCV002647324	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-15	criteria provided, single submitter	clinical testing	The p.W1858* pathogenic mutation (also known as c.5573G>A), located in coding exon 36 of the ATM gene, results from a G to A substitution at nucleotide position 5573. This changes the amino acid from a tryptophan to a stop codon within coding exon 36. This mutation was reported in the compound heterozygous state in an individual with isolated segmental dystonia, but without ataxia and telangiectasia (Necpál J et al. Mov. Disord. Clin. Pract. Dec;5:89-91). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV004020927	SCV004931242	pathogenic	Familial cancer of breast	2024-01-25	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.