Submissions for variant NM_000051.4(ATM):c.5441dup (p.Leu1814fs)

dbSNP: rs1555106508

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564879	SCV000667932	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing	The c.5441dupT pathogenic mutation, located in coding exon 35 of the ATM gene, results from a duplication of T at nucleotide position 5441, causing a translational frameshift with a predicted alternate stop codon (p.L1814Ffs*9). This mutation (designated as 5441insT) has been reported in an individual with a clinical diagnosis of ataxia telangiectasia (Sandoval N et al. Hum Mol Genet, 1999 Jan;8:69-79). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564879	SCV000687619	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-08	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 36 of the ATM gene, creating a frameshift and 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 an individual affected with ataxia telangiectasia (PMID: 9887333). 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.
Invitae	RCV001858237	SCV002229189	pathogenic	Ataxia-telangiectasia syndrome	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1814Phefs*9) 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: 9887333). This variant is also known as 5441insT. ClinVar contains an entry for this variant (Variation ID: 482601). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004024496	SCV004931665	pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.