ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4802G>A (p.Ser1601Asn) (rs587782506)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131649 SCV000186676 likely benign Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
Color RCV000131649 SCV000910699 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000236820 SCV000292997 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.4802G>A at the cDNA level, p.Ser1601Asn (S1601N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has been observed in at least two individuals with breast cancer, in an individual with chronic lymphocytic leukemia, and in a Middle Eastern individual with no known history of genetic disease (Thorstenson 2001, Paglia 2010, Skowronska 2012, Decker 2017). ATM Ser1601Asn 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 Ser1601Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779764 SCV000916546 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The ATM c.4802G>A (p.Ser1601Asn) variant involves the alteration of a non-conserved nucleotide located in the Lipovitellin-phosvitin complex-like, superhelical domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/246614 control chromosomes at a frequency of 0.0000324, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was reported in one breast cancer patient and one CLL patient in the literature, without strong evidence for causality (Paglia_2011, Skowronska_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain signfiicance. Taken together, this variant is classified as VUS.
Invitae RCV000205840 SCV000260967 uncertain significance Ataxia-telangiectasia syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1601 of the ATM protein (p.Ser1601Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs587782506, ExAC 0.006%). This variant was reported in an individual affected with breast cancer (PMID: 19404735), as well as an unaffected individual (PMID: 11443540). ClinVar contains an entry for this variant (Variation ID: 142501). 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 asparagine amino acid residue is 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. 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.
Mendelics RCV000205840 SCV000838548 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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