ClinVar Miner

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

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Total submissions: 5
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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 2019-08-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
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 2020-01-03 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 RCV000220769 SCV000910967 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing

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