ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8734A>G (p.Arg2912Gly) (rs376676328)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131723 SCV000186763 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131723 SCV000292188 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515325 SCV000611371 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000656766 SCV000209663 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.8734A>G at the cDNA level, p.Arg2912Gly (R2912G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has been observed in individuals with breast, endometrial, pancreatic, colorectal, or other cancers (Bernstein 2003, Goldgar 2011, Couch 2015, Ring 2016, Tung 2016, Hu 2016, Yurgelun 2017, Villacis 2017, Tiao 2017, Young 2018). Case-control studies have identified ATM Arg2912Gly in several individuals with breast cancer, but found the variant to be rare or absent in healthy controls (Pylkas 2007, Tavtigian 2009, Decker 2017). Segregation analysis by Pylkas et al. (2007) identified this variant in all but one of the affected individuals within two breast cancer kindreds. However, at least two breast cancer patients with ATM Arg2912Gly have also been found to harbor pathogenic variants in either BRCA1 or BRIP1 (Thorstenson 2003, Zidan 2017), and Goldgar et al. (2011) found retention of the wild type allele in studied breast tumors. In vivo functional analyses found that ATM Arg2912Gly showed a partial defect in kinase activity, but normal ATM expression and protein stability, no dominant-negative effect, and no increased sensitivity to irradiation (Pylkas 2007). ATM Arg2912Gly was observed at an allele frequency of 0.04% (53/126,696) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the kinase 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 Arg2912Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000131723 SCV000821881 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000120167 SCV000084309 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000122892 SCV000166150 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2912 of the ATM protein (p.Arg2912Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs376676328, ExAC 0.05%), including a homozygous individual. This variant has been reported in an individual with endometrial cancer (PMID: 27443514), and individuals and families affected with breast cancer, with some evidence of segregation with disease (PMID: 11505391, 12810666, 17166884, 21787400, 12673797). ClinVar contains an entry for this variant (Variation ID: 133641). An experimental study has shown that this variant does not affect protein stability, but partially affects the kinase activity of ATM in vitro (PMID: 17166884). 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.

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