ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2770C>T (p.Arg924Trp) (rs55723361)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115163 SCV000185861 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000115163 SCV000682075 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Counsyl RCV000232085 SCV000795286 uncertain significance Ataxia-telangiectasia syndrome 2017-11-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763692 SCV000894572 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000590158 SCV000149072 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.2770C>T at the cDNA level, p.Arg924Trp (R924W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been identified in breast, colon, sarcoma, and renal cancer patients (Greenman 2007, Pearlman 2016, Chan 2017, Jalkh 2017). ATM Arg924Trp was observed at an allele frequency of 0.06% (6/10150) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). ATM Arg924Trp is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg924Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590158 SCV000694234 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The ATM c.2770C>T (p.Arg924Trp) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in an armadillo-type fold domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000494 (6/121406 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been identified in cancer patients in several published reports, however without strong evidence for pathogenicity in multiple cancer types (e.g., Greenman_Nature_2007; Jalkh_BMC Med Genom_2017; Bernstein_JNCI_2010). To our knowledge, no functional studies have been performed to aid in the classification of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000232085 SCV000282911 uncertain significance Ataxia-telangiectasia syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 924 of the ATM protein (p.Arg924Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs55723361, ExAC 0.007%). This variant has been reported in individuals affected with breast cancer and colon cancer (PMID: 28202063, 27978560, 20305132). It has also been reported in an individuals affected with diffuse large B-cell lymphoma, as well as control individuals in the same study (PMID: 28211887). ClinVar contains an entry for this variant (Variation ID: 127358). 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 disruptive, 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.
Mendelics RCV000232085 SCV000838510 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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