ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3295G>A (p.Asp1099Asn) (rs372966951)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214286 SCV000278510 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000214286 SCV000910978 likely benign Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000590021 SCV000564627 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.3295G>A at the cDNA level, p.Asp1099Asn (D1099N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant was observed in 2/4,112 breast cancer cases and 0/2,399 controls in a meta-analysis, as well as in an individual with colorectal cancer (Tavtigian 2009, Yurgelun 2017). ATM Asp1099Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asp1099Asn is located in the beta-adaptin interaction region (Tavtigian 2009). 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 Asp1099Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590021 SCV000694254 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The ATM c.3295G>A (p.Asp1099Asn) variant involves the alteration of a conserved nucleotide. 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 4/85168 control chromosomes at a frequency of 0.000047, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant has been reported in multiple affected individuals 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.
Invitae RCV000168114 SCV000218770 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1099 of the ATM protein (p.Asp1099Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs372966951, ExAC 0.03%). This variant has been reported in isolated individuals affected with breast cancer (PMID: 19781682, 21787400) and colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 188196). 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 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.

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