ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.875C>T (p.Pro292Leu) (rs747727055)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220769 SCV000273133 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-04 criteria provided, single submitter clinical testing The p.P292L variant (also known as c.875C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 875. The proline at codon 292 is replaced by leucine, an amino acid with similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in ataxia-telangiectasia (A-T) patients, two of whom have had a typical phenotype and two of whom had a mild phenotype (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Schon K et al. Ann. Neurol., 2019 02;85:170-180). Functional analyses of p.P292L have shown reduced kinase activity, reduced protein levels, and increased radiosensitivity compared to wildtype ATM (Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Barone G et al. Hum. Mutat., 2009 Aug;30:1222-30). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000255507 SCV000322064 likely pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.875C>T at the cDNA level, p.Pro292Leu (P292L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). ATM Pro292Leu has been observed in the compound heterozygous state in at least one child with classic ataxia telangiectasia, one with a mild presentation of ataxia telangiectasia, and one who presented with severe combined immunodeficiency in infancy (Stankovic 1998, Sun 2002, Mitui 2009, Mallott 2013). Functional studies have shown this variant to have reduced ATM protein levels and reduced or absent kinase activity (Stankovic 1998, Barone 2009, Mitui 2009, Reiman 2011). Additionally, ATM Pro292Leu was consistently shown to exhibit higher levels of radiosensitivity after exposure to ionizing radiation than normal cells (Becker-Catania 2000, Mitui 2009). ATM Pro292Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider ATM Pro292Leu to be a likely pathogenic variant.
Invitae RCV000526404 SCV000622847 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 292 of the ATM protein (p.Pro292Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs747727055, ExAC 0.01%). This variant has been observed in several individuals with a milder phenotype of ataxia telangiectasia (A-T), with a second pathogenic ATM variant (PMID: 19431188, 18634022, 10873394, 30549301) and an individual with severe combined immunodeficiency and A-T (PMID: 23264026). This variant is also known as 1260C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 229794). Experimental studies have shown that this missense change causes unstable ATM expression, reduced kinase activity, elevated radiosensitivity, intermediate checkpoint activity, and interfered phosphorylation on other proteins, when transfected into lymphoblastoid cells lacking ATM activity (PMID: 19431188, 18634022). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000526404 SCV000800812 likely pathogenic Ataxia-telangiectasia syndrome 2018-05-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220769 SCV000910967 pathogenic Hereditary cancer-predisposing syndrome 2020-11-11 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 292 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown instability and low-level expression of the mutant protein, and absent or reduced kinase activity, as well as high radiosensitivity after ionizing radiation exposure of cells carrying this variant (PMID 18634022, 19431188). This variant has been reported in individuals affected with classic or mild form of ataxia-telangiectasia (PMID: 10873394, 18634022, 23264026, 30549301) and in individuals affected with breast cancer (PMID: 32957588; Color internal data). This variant has been identified in 3/279556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255507 SCV001448023 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255507 SCV001742991 likely pathogenic not provided no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001658022 SCV001877094 likely pathogenic Breast carcinoma no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000255507 SCV001955994 likely pathogenic not provided no assertion criteria provided clinical testing

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