Submissions for variant NM_000051.4(ATM):c.2880del (p.Leu961fs)

dbSNP: rs730881300

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497266	SCV000209616	pathogenic	not provided	2018-11-15	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]TTGC. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 961 and creates a premature stop codon at position 10 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.2880delC has been reported in a compound heterozygous state in individuals with ataxia telangiectasia (Laake 2000, Stray-Pedersen 2004), as well as in an individual with pancreatic cancer (Hu 2016). We therefore consider this variant to be pathogenic.
Counsyl	RCV000412201	SCV000486873	likely pathogenic	Ataxia-telangiectasia syndrome	2016-08-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000159629	SCV000581448	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	clinical testing	The c.2880delC pathogenic mutation, located in coding exon 18 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 2880, causing a translational frameshift with a predicted alternate stop codon (p.L961Cfs*10). This alteration has been detected in the compound heterozygous state in two Norwegian individuals with ataxia-telangiectasia (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Stray-Pedersen A et al. Clin. Exp. Immunol. 2004 Jul;137:179-86). This alteration has also been reported in a breast cancer patient and a pancreatic cancer patient who underwent hereditary cancer multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412201	SCV000622373	pathogenic	Ataxia-telangiectasia syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) 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 present in population databases (rs758561876, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and pancreatic cancers (PMID: 10980530, 17376192, 26483394, 26681312). ClinVar contains an entry for this variant (Variation ID: 181871). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000159629	SCV000905170	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 19 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 individuals affected with ataxia-telangiectasia (PMID: 10980530), breast cancer (PMID: 26681312), and pancreatic cancer (PMID: 26483394). This variant has been identified in 1/251426 chromosomes 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.
Myriad Genetics, Inc.	RCV004019932	SCV004933430	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000412201	SCV002076459	pathogenic	Ataxia-telangiectasia syndrome	2021-07-29	no assertion criteria provided	clinical testing