ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7740A>C (p.Arg2580Ser) (rs199915459)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589821 SCV000149163 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.7740A>C at the cDNA level, p.Arg2580Ser (R2580S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant has been observed in individuals with breast or ovarian cancer (Lu 2015, Tung 2016). ATM Arg2580Ser was observed at an allele frequency of 0.03% (11/34,414) in individuals of Latino ancestry 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 Arg2580Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115254 SCV000186651 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000205594 SCV000261019 uncertain significance Ataxia-telangiectasia syndrome 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 2580 of the ATM protein (p.Arg2580Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs199915459, ExAC 0.02%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 26976419, 26689913). ClinVar contains an entry for this variant (Variation ID: 127448). 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. 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.
Integrated Genetics/Laboratory Corporation of America RCV000589821 SCV000694357 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.7740A>C (p.Arg2580Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not available) although these predictions have yet to be functionally assessed. The variant of interest is located outside of any known functional domain or repeat. The variant of interest has been found in a large, broad control population, ExAC in 5/121060 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia or 1/1999 for hereditary breast and/or ovarian cancer. The variant of interest has been reported in publications in BrC patients, although with limited information (ie lack of phenotypic, co-occurrence and co-segregation data), however, multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
GeneKor MSA RCV000115254 SCV000821873 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000205594 SCV000838596 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000589821 SCV000840963 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing
Color RCV000115254 SCV000902816 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing

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