ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2880del (p.Leu961fs) (rs730881300)

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Total submissions: 5
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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.
Invitae RCV000412201 SCV000622373 pathogenic Ataxia-telangiectasia syndrome 2018-09-07 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. This variant is present in population databases (rs758561876, ExAC 0.001%). This variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 10980530, 17376192), and in heterozygous individuals with breast and pancreatic cancers (PMID: 26681312, 26483394). ClinVar contains an entry for this variant (Variation ID: 181871). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000159629 SCV000905170 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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