ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3242A>G (p.Asn1081Ser) (rs368111672)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130850 SCV000185748 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130850 SCV000902741 likely benign Hereditary cancer-predisposing syndrome 2015-06-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515162 SCV000611358 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000588298 SCV000209719 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.3242A>G at the cDNA level, p.Asn1081Ser (N1081S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at least one individual with ataxia telangiectasia, in co-occurrence with unspecified biallelic ATM variants (Jeddane 2013). It has also been reported in two breast cancer cases, but was absent from healthy controls (Decker 2017). ATM Asn1081Ser was observed at an allele frequency of 0.13% (41/30,780) in individuals of South Asian ancestry 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 Asn1081Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588298 SCV000694253 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The ATM c.3242A>G (p.Asn1081Ser) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 26/121284 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.001334 (22/16494). This frequency is about 1 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant was reported in the literature in one AT patient and was described as a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000475427 SCV000546670 uncertain significance Ataxia-telangiectasia syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1081 of the ATM protein (p.Asn1081Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs368111672, ExAC 0.1%). This variant has been observed as a polymorphism in an individual with ataxia-telangiectasia (PMID: 23322442). ClinVar contains an entry for this variant (Variation ID: 142046). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.

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