ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000122846 SCV000166104 likely benign Ataxia-telangiectasia syndrome 2020-01-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115185 SCV000185691 likely benign Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing 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)
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 RCV000212008 SCV000694272 uncertain significance not specified 2019-05-14 criteria provided, single submitter clinical testing Variant summary: ATM c.4066A>G (p.Asn1356Asp) results in a conservative amino acid change located in the Armadillo-type fold domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248760 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.4066A>G has been reported in the literature in individuals affected with Breast Cancer and Lynch syndrome (Yurgelun_2015, Goldgar_2011, Sommer_2003, Tavtigian_2009, Caminsky_2016, Decker_2017, Lu_2015, Tung_2015, O'Leary_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 del exons 8-15). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics Inc RCV000586490 SCV000840937 uncertain significance not provided 2019-02-15 criteria provided, single submitter clinical testing
Color RCV000115185 SCV000902670 likely benign Hereditary cancer-predisposing syndrome 2016-02-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586490 SCV001148418 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122846 SCV001262666 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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