ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2396C>T (p.Ala799Val) (rs199954262)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159693 SCV000216440 likely benign Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000159693 SCV000903122 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000254631 SCV000209701 likely benign not specified 2017-12-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
GeneKor MSA RCV000159693 SCV000821838 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587364 SCV000694221 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.2396C>T variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.005% which does not exceed the maximal expected allele frequency for a pathogenic variant in ATM (0.05%). The variant has been reported in one publication in a patient who also carried a pathogenic MSH2 mutation (Yurgelun_2015). One reputable clinical lab has classified the variant as a VUS while another has classified it as likely benign, without evidence to independently evaluate. Taken together, until additional clinical and/or functional data becomes available, this variant has been classified as a VUS.
Invitae RCV000472551 SCV000547139 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 799 of the ATM protein (p.Ala799Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs199954262, ExAC 0.009%). This variant has been reported in an individual affected with renal clear cell carcinoma (PMID: 26689913), and in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 181928). 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 valine 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.
True Health Diagnostics RCV000159693 SCV000787852 likely benign Hereditary cancer-predisposing syndrome 2017-10-30 no assertion criteria provided clinical testing

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