ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3689A>G (p.Asn1230Ser) (rs587782195)

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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 RCV000130847 SCV000185745 likely benign Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000130847 SCV000910931 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
GeneDx RCV000587182 SCV000209782 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.3689A>G at the cDNA level, p.Asn1230Ser (N1230S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has been observed in several individuals with breast cancer and was absent among 5488 controls in a breast cancer case-control study (Decker 2017, Hauke 2018). ATM Asn1230Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (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 Asn1230Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587182 SCV000694264 uncertain significance not provided 2015-10-16 criteria provided, single submitter clinical testing Variant summary: The c.3689A>G in ATM gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant of interest was not found in control population of ExAC. The variant of interest has been reported as VUS by several independent reputable database/clinical laboratories. More definitive data are needed. Taking together, the variant was classified as VUS until more information becomes available.
Invitae RCV000200096 SCV000254090 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1230 of the ATM protein (p.Asn1230Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142043). 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 serine 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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