Submissions for variant NM_000051.4(ATM):c.5973A>C (p.Glu1991Asp)

dbSNP: rs587782274

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131129	SCV000186061	likely benign	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000484990	SCV000567578	uncertain significance	not provided	2016-03-30	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5973A>C at the cDNA level, p.Glu1991Asp (E1991D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic or benign variant. However, this variant has been reported as a somatic variant in clear cell renal cell carcinoma (Greenman 2007, Dalgliesh 2010). ATM Glu1991Asp 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 Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. ATM Glu1991Asp occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Glu1991Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000131129	SCV000687663	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1991 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/246054 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035231	SCV001198551	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1991 of the ATM protein (p.Glu1991Asp). This variant is present in population databases (rs587782274, gnomAD 0.0009%). 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: 142164). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359251	SCV005919187	uncertain significance	Familial cancer of breast	2024-08-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001035231	SCV002077975	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-23	no assertion criteria provided	clinical testing