ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5882A>G (p.Tyr1961Cys) (rs56399311)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589184 SCV000149127 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted ATM c.5882A>G at the cDNA level, p.Tyr1961Cys (Y1961C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been observed in individuals with breast cancer, pancreatic cancer, and chronic lymphocytic leukemia (Skowronska 2012, Grant 2015, Decker 2017, Chaffee 2018). Additionally, Barone et al. (2009) reported that ATM Tyr1961Cys results in reduced kinase activity in an in vitro assay. ATM Tyr1961Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Tyr1961Cys is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr1961Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115218 SCV000186207 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000195828 SCV000254125 uncertain significance Ataxia-telangiectasia syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1961 of the ATM protein (p.Tyr1961Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs56399311, ExAC 0.006%). This variant has been reported in individuals affected with pancreatic cancer, chronic lymphocytic leukemia, and T-cell lymphoblastic leukemia (PMID: 25479140, 9622061, 21933854). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 127413). In an experimental study, this variant demonstrated reduced ATM kinase activity (PMID: 19431188). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000115218 SCV000292183 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589184 SCV000694308 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.5882A>G (p.Tyr1961Cys) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 4/121852 control chromosomes at a frequency of 0.0000328, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant has been reported in multiple patients with CLL, breast cancer, or pancreatic cancer, without strong evidence supporting pathogenicity of this variant. One publication lists the variant as having reduced ATM Kinase activity but does not provide data supporting this statement. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000195828 SCV000790368 uncertain significance Ataxia-telangiectasia syndrome 2017-03-16 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115218 SCV000821861 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000195828 SCV000838560 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763707 SCV000894587 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing

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