Submissions for variant NM_000051.4(ATM):c.8959G>T (p.Asp2987Tyr)

dbSNP: rs863224582

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525512	SCV000622867	uncertain significance	Ataxia-telangiectasia syndrome	2022-06-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2987 of the ATM protein (p.Asp2987Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 453755). 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 C15"). 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	RCV000570783	SCV000660751	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.D2987Y variant (also known as c.8959G>T), located in coding exon 61 of the ATM gene, results from a G to T substitution at nucleotide position 8959. The aspartic acid at codon 2987 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not 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.
Illumina Laboratory Services, Illumina	RCV000525512	SCV001264812	uncertain significance	Ataxia-telangiectasia syndrome	2018-03-30	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000570783	SCV001343916	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 2987 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 1/251392 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.
Genome-Nilou Lab	RCV000525512	SCV001781326	uncertain significance	Ataxia-telangiectasia syndrome	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001764521	SCV002000953	uncertain significance	not provided	2020-03-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000570783	SCV004228063	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568690	SCV005056933	uncertain significance	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000525512	SCV002083143	uncertain significance	Ataxia-telangiectasia syndrome	2021-04-13	no assertion criteria provided	clinical testing