ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7327C>T (p.Arg2443Ter) (rs121434220)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003175 SCV000220525 likely pathogenic Ataxia-telangiectasia syndrome 2014-07-19 criteria provided, single submitter literature only
Invitae RCV000003175 SCV000260860 pathogenic Ataxia-telangiectasia syndrome 2019-12-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2443*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 8808599, 10817650, 9887333, 21833744, 14586414), and individuals with prostate, breast, and pancreatic cancer (PMID: 24556621, 26822949, 26483394). ClinVar contains an entry for this variant (Variation ID: 3036). Experimental studies in heterozygous cell lines have shown that this nonsense change causes reduced ATM protein and mRNA expression, and increased sensitivity to radiation (PMID: 15101044, 14970866). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000220229 SCV000273030 pathogenic Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
GeneDx RCV000484232 SCV000566496 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7327C>T at the cDNA level and p.Arg2443Ter (R2443X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with ataxia-telangiectasia (Sandoval 1999, Bernstein 2003, Anheim 2010, Tariq 2018) and in the heterozygous state in individuals with breast, pancreatic, and/or prostate cancer (Leongamornlert 2014, Hu 2016, Lhota 2016). We consider this variant to be pathogenic.
Color RCV000220229 SCV000687767 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003175 SCV000694350 pathogenic Ataxia-telangiectasia syndrome 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This prediction has been confirmed by one study showing that the ATM protein is absent in cells from a patient who carries the variant of interest and a frameshift variant (Prodosmo_2013). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7517_7520delGAGA, c.8264_8268delATAAG). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple AT patients and is absent in 119996 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000484232 SCV000805612 pathogenic not provided 2017-07-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484232 SCV001246116 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001250440 SCV001424815 pathogenic Familial cancer of breast 2019-04-15 criteria provided, single submitter clinical testing The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic.
OMIM RCV000003175 SCV000023333 pathogenic Ataxia-telangiectasia syndrome 1999-01-01 no assertion criteria provided literature only

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