Submissions for variant NM_000051.4(ATM):c.2571_2572del (p.Leu857_Phe858insTer)

dbSNP: rs1555082257

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657842	SCV000779598	likely pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing	This deletion of two nucleotides is denoted ATM c.2571_2572delAT at the cDNA level and p.Phe858Ter (F858X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATCT[delAT]TTAA. The deletion creates a nonsense variant, which changes a Phenylalanine to a premature stop codon. Although this variant has not been previously reported to our knowledge, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider ATM c.2571_2572delAT to be likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000657842	SCV002067371	likely pathogenic	not provided	2019-08-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a 2 base pair deletion in exon 17, c.2571_2572del. This deletion results in the creation of a premature stop codon at amino acid position 858, p.Phe858*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. This sequence change has not been previously described in patients with ATM-related disorders; however, truncating sequence changes are commonly reported in association with ATM-related cancer susceptibility and ataxia telangiectasia (PMIDs: 30287823, 22213089, 29506128, 28724667, 23807571,and others). The p.Phe858* change has not been described in the population databases (ExAC and gnomAD). These collective evidences indicate that this sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003605672	SCV004424231	pathogenic	Ataxia-telangiectasia syndrome	2023-01-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 546062). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe858*) 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).