ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9008A>G (p.Asn3003Ser) (rs144636562)

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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 RCV000221585 SCV000274748 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000531722 SCV000791957 uncertain significance Ataxia-telangiectasia syndrome 2017-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000159669 SCV000209670 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.9008A>G at the cDNA level, p.Asn3003Ser (N3003S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant was observed in an individual with breast cancer as well as in 1/4,112 breast cancer cases and 0/2,399 controls in a large meta-analysis (Tavtigian 2009, Caminsky 2016). It was also observed in an individual with sporadic acute lymphoblastic leukemia and in three siblings with malignant melanoma (Goldstein 2017, Ratnaparkhe 2017). ATM Asn3003Ser was not observed in large population cohorts (Lek 2016). This variant is located in the FATC 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 Asn3003Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000531722 SCV000622876 uncertain significance Ataxia-telangiectasia syndrome 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 3003 of the ATM protein (p.Asn3003Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs144636562, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 181905). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
True Health Diagnostics RCV000221585 SCV000787885 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing

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