Submissions for variant NM_000051.4(ATM):c.241A>G (p.Asn81Asp)

gnomAD frequency: 0.00001  dbSNP: rs758962678

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166809	SCV000217623	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-05	criteria provided, single submitter	clinical testing	The p.N81D variant (also known as c.241A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 241. The asparagine at codon 81 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10). This alteration was also detected in a study of 1054 BRCA-mutation-negative Hispanic women with hereditary breast cancer and 312 local and 887 multi-ethnic controls (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). Experiments conducted in fibroblast and lymphoblast cells indicate that an ATM construct containing four missense alterations, including N81D, maintained kinase activity and the ability to bind p53 (Fernandes N et al. J. Biol. Chem. 2005 Apr;280:15158-64). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457539	SCV000546942	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 81 of the ATM protein (p.Asn81Asp). This variant is present in population databases (rs758962678, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 30262796, 31206626). ClinVar contains an entry for this variant (Variation ID: 187119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000482292	SCV000570892	uncertain significance	not provided	2021-11-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast cancer (Quezada Urban 2018, Weitzel 2019); This variant is associated with the following publications: (PMID: 27720647, 31658756, 31206626, 30262796, 15713674)
Color Diagnostics, LLC DBA Color Health	RCV000166809	SCV000687385	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 81 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. However, an ATM variant protein containing four missense mutations between codons 81 to 87, including p.Asn81Asp, has been shown to be similar to wild-type in kinase and p53 binding assays and survival after ionizing radiation exposure (PMID: 15713674). This variant has been observed in individuals suspected of hereditary breast and ovarian cancer (PMID: 30262796) and hereditary cancer (PMID: 27720647). This variant has been identified in 19/250838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731415	SCV001983580	uncertain significance	not specified	2021-09-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.241A>G (p.Asn81Asp) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250838 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.241A>G has been reported in the literature in individuals affected with breast cancer or other cancer (e.g. Mu_2016, QuezadaUrban_2018, Weitzel_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462226	SCV004204534	uncertain significance	Familial cancer of breast	2024-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482292	SCV004220862	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00055 (19/34506 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer and in a control individual (PMID: 31206626 (2019)), also in individuals with suspected hereditary cancer or breast/ovarian cancer (PMIDs: 30262796 (2018), 27720647 (2015)). Additionally, this variant was assessed in a functional study, however, the results do not conclusively indicate a pathogenic role for this variant (PMID: 15713674 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Athena Diagnostics	RCV000482292	SCV004229180	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant was found in a cell line and showed impaired ATM activity and reduced p53 binding, but it is unclear how this may affect disease. (PMID: 15713674)
Natera, Inc.	RCV000457539	SCV002088332	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-06	no assertion criteria provided	clinical testing