Submissions for variant NM_000051.4(ATM):c.1524del (p.Gly509fs)

dbSNP: rs786204737

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169584	SCV000221089	likely pathogenic	Ataxia-telangiectasia syndrome	2015-01-27	criteria provided, single submitter	literature only
GeneDx	RCV000236634	SCV000293432	likely pathogenic	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in ATM is denoted c.1524delT at the cDNA level and p.Gly509GlufsX3 (G509EfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is TACT[T]GGAG. The deletion causes a frameshift which changes a Glycine to a Glutamic Acid at codon 509, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.1524delT, also published as ATM Leu508LeufsX4, has been observed in at least one individual with Ataxia Telangiectasia (Cavalieri 2008). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169584	SCV000622267	pathogenic	Ataxia-telangiectasia syndrome	2023-09-17	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: 189158). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 16941484). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly509Glufs*3) 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).
Ambry Genetics	RCV000573650	SCV000665463	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The c.1524delT pathogenic mutation, located in coding exon 9 of the ATM gene, results from a deletion of one nucleotide at position 1524, causing a translational frameshift with a predicted alternate stop codon (p.G509Efs*3). This mutation was detected in conjunction with a second ATM mutation in an Italian individual with ataxia-telangiectasia (Cavalieri S et al, Hum. Mutat. 2006 Oct; 27(10):1061). 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	RCV000573650	SCV001349858	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169584	SCV001448433	pathogenic	Ataxia-telangiectasia syndrome	2020-11-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1524delT (p.Gly509GlufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251190 control chromosomes (gnomAD). c.1524delT has been reported in the literature in individuals affected with Ataxia-Telangiectasia, breast cancer and ovarian cancer (Cavalieri_2006, Rizzolo_2019, Bochtler_2019, Arvai_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003462269	SCV004206891	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462269	SCV004931634	pathogenic	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.