Submissions for variant NM_000051.4(ATM):c.3832G>A (p.Asp1278Asn)

gnomAD frequency: 0.00001  dbSNP: rs730881365

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159718	SCV000209730	uncertain significance	not provided	2016-10-27	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3832G>A at the cDNA level, p.Asp1278Asn (D1278N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp1278Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Asp1278Asn occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Asp1278Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234345	SCV000282943	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1278 of the ATM protein (p.Asp1278Asn). This variant is present in population databases (rs730881365, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 181951). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV000566259	SCV000667863	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-17	criteria provided, single submitter	clinical testing	The p.D1278N variant (also known as c.3832G>A), located in coding exon 25 of the ATM gene, results from a G to A substitution at nucleotide position 3832. The aspartic acid at codon 1278 is replaced by asparagine, an amino acid with highly similar properties. 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.
Counsyl	RCV000234345	SCV000794783	uncertain significance	Ataxia-telangiectasia syndrome	2017-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566259	SCV001359399	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1278 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. This variant has been reported in an individual affected with hereditary breast and ovarian cancer in the literature (PMID: 29522266). This variant has been identified in 1/31388 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.
Genetic Services Laboratory, University of Chicago	RCV001818353	SCV002065328	uncertain significance	not specified	2021-06-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.3832G>A, in exon 26 that results in an amino acid change, p.Asp1278Asn. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the African/African American subpopulation (dbSNP rs730881365). The p.Asp1278Asn change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp1278Asn substitution. This sequence change does not appear to have been previously described in patients with ATM-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp1278Asn change remains unknown at this time
Baylor Genetics	RCV003474817	SCV004200736	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000234345	SCV001458195	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing