ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2924A>G (p.Asn975Ser) (rs730881354)

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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 RCV000569201 SCV000665657 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000569201 SCV000913911 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000469650 SCV000797924 uncertain significance Ataxia-telangiectasia syndrome 2018-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000159704 SCV000209715 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.2924A>G at the cDNA level, p.Asn975Ser (N975S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in breast cancer cases and controls (Tavtigian 2009, Decker 2017). ATM Asn975Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn975Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469650 SCV000547050 uncertain significance Ataxia-telangiectasia syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 975 of the ATM protein (p.Asn975Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (rs730881354, ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 181937). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this missense variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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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