ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.928A>G (p.Ser310Gly) (rs745773225)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219840 SCV000273551 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000219840 SCV000687882 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000481289 SCV000569907 uncertain significance not provided 2016-04-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.928A>G at the cDNA level, p.Ser310Gly (S310G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ser310Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ser310Gly occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Ser310Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167964 SCV000218612 uncertain significance Ataxia-telangiectasia syndrome 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 310 of the ATM protein (p.Ser310Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs745773225, ExAC 0.02%). This variant has been observed in an individual with breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in ATM, which suggests that this c.928A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 188110). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, 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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