ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2275A>G (p.Ser759Gly) (rs148705269)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589762 SCV000149060 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.2275A>G at the cDNA level, p.Ser759Gly (S759G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant was observed in at least three individuals undergoing multi-gene cancer panel testing due to a history of breast cancer (Caminsky 2016, Tung 2016), as well as in an individual with a personal and family history of pancreatic cancer (Chaffee 2018). ATM Ser759Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ser759Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115151 SCV000183888 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205470 SCV000259588 uncertain significance Ataxia-telangiectasia syndrome 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 759 of the ATM protein (p.Ser759Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs148705269, ExAC 0.005%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26976419, 26898890), and an individual with low grade glioma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127346). 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.
Illumina Clinical Services Laboratory,Illumina RCV000205470 SCV000367035 uncertain significance Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics,Fulgent Genetics RCV000515206 SCV000611350 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000115151 SCV000682046 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589762 SCV000694214 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The ATM c.2275A>G (p.Ser759Gly) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121228 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

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