Submissions for variant NM_000051.4(ATM):c.5416del (p.Trp1805_Ile1806insTer)

dbSNP: rs879254041

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235542	SCV000293267	likely pathogenic	not provided	2017-06-13	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted ATM c.5416delA at the cDNA level and p.Ile1806Ter (I1806X) at the protein level. The normal sequence, with the base that is deleted in braces, is TTGG[A]TAAA. The deletion creates a nonsense variant, which changes an Isoleucine 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, and is considered likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001188317	SCV001355345	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 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 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.
Ambry Genetics	RCV001188317	SCV002653993	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The c.5416delA pathogenic mutation, located in coding exon 35 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 5416, causing a translational frameshift with a predicted alternate stop codon (p.I1806*). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003463698	SCV004216235	likely pathogenic	Familial cancer of breast	2021-05-29	criteria provided, single submitter	clinical testing
Invitae	RCV003605615	SCV004376067	pathogenic	Ataxia-telangiectasia syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ATM-related conditions (PMID: 32853339). ClinVar contains an entry for this variant (Variation ID: 246001). 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. This sequence change creates a premature translational stop signal (p.Ile1806*) 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).
Myriad Genetics, Inc.	RCV003463698	SCV004930720	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235542	SCV001551132	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The ATM p.Ile1806* variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs879254041) as “With Likely pathogenic allele”, and ClinVar (as likely pathogenic by GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ile1806 variant leads to a premature stop codon at position 1806 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.