Submissions for variant NM_000051.4(ATM):c.2579A>T (p.Asp860Val)

dbSNP: rs761251711

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232136	SCV000282905	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 860 of the ATM protein (p.Asp860Val). This variant is present in population databases (rs761251711, 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: 236692). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV000479651	SCV000567485	uncertain significance	not provided	2017-09-25	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2579A>T at the cDNA level, p.Asp860Val (D860V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp860Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Asp860Val occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Asp860Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574247	SCV000660677	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-13	criteria provided, single submitter	clinical testing	The p.D860V variant (also known as c.2579A>T), located in coding exon 16 of the ATM gene, results from an A to T substitution at nucleotide position 2579. The aspartic acid at codon 860 is replaced by valine, an amino acid with highly dissimilar 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.
Color Diagnostics, LLC DBA Color Health	RCV000574247	SCV000904596	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 860 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 1/251436 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.
Fulgent Genetics, Fulgent Genetics	RCV002503882	SCV002815134	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003238746	SCV003936120	uncertain significance	Colorectal cancer, susceptibility to, 1	2023-07-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with valine at codon 860 of the ATM protein (p.Asp860Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs761251711, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with ATMrelated conditions. ClinVar contains an entry for this variant (Variation ID: 236692). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C0"). Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004547575	SCV004113968	uncertain significance	ATM-related disorder	2023-04-08	criteria provided, single submitter	clinical testing	The ATM c.2579A>T variant is predicted to result in the amino acid substitution p.Asp860Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108138010-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000232136	SCV002076275	uncertain significance	Ataxia-telangiectasia syndrome	2021-04-06	no assertion criteria provided	clinical testing