ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4066A>G (p.Asn1356Asp) (rs147600485)

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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 RCV000115185 SCV000185691 likely benign Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,In silico models in agreement (benign)
Athena Diagnostics Inc RCV000586490 SCV000840937 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing
Color RCV000115185 SCV000902670 likely benign Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000586490 SCV000149094 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.4066A>G at the cDNA level, p.Asn1356Asp (N1356D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has been observed in individuals with breast cancer, lung cancer, or advanced cancer of unknown primary, and was identified in 13/13,087 cases and 5/5488 controls in a breast cancer case-control study (Sommer 2003, Tavtigian 2009, Lu 2015, Caminsky 2016, Decker 2017, Mandelker 2017). Yurgelun et al. (2015) reported this variant in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps who also harbored a pathogenic MSH2 variant. ATM Asn1356Asp was also observed in 1/962 European individuals undergoing whole genome sequencing, with no specific information about cancer history (Yu 2015). This variant was observed at an allele frequency of 0.03% (33/124,140) in individuals of European 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 Asn1356Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000212008 SCV000593502 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586490 SCV000694272 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The ATM c.4066A>G (p.Asn1356Asp) variant located in the Armadillo-type fold domain causes a missense change involving a non-conserved nucleotide, which 5/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 17/120994 (1/7117), predominantly in the European (Non-Finnish) cohort, 16/66528 (1/4158), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999 for Breast Cancer. Multiple publications have cited the variant in affected individuals including 1 individual that had a co-occurrence with a MSH2 deletion of exons 8-15. In addition, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000122846 SCV000166104 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 1356 of the ATM protein (p.Asn1356Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs147600485, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 12935922, 19781682, 28779002), head and neck squamous cell carcinoma, and low grade glioma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127380). 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 aspartic acid 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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