Submissions for variant NM_000051.4(ATM):c.1726A>G (p.Ile576Val)

gnomAD frequency: 0.00001  dbSNP: rs1064795170

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486868	SCV000570699	uncertain significance	not provided	2024-09-22	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28281318, 32885271, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000582520	SCV000687322	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 576 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 adrenal neuroblastoma (PMID: 28281318). In an international breast cancer case-control meta-analysis, this variant has been detected in 1/60466 cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251152 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	RCV000690771	SCV000818497	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 576 of the ATM protein (p.Ile576Val). This variant is present in population databases (no rsID available, gnomAD 0.03%). 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: 421483). 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	RCV000582520	SCV001173423	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	The p.I576V variant (also known as c.1726A>G), located in coding exon 10 of the ATM gene, results from an A to G substitution at nucleotide position 1726. The isoleucine at codon 576 is replaced by valine, an amino acid with highly similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486868	SCV001473239	uncertain significance	not provided	2019-09-04	criteria provided, single submitter	clinical testing	The ATM c.1726A>G; p.Ile576Val variant (rs1064795170) has been found in intracranial myxoid mesenchymal tumor tissue in a patient who had a history of adrenal neuroblastoma (Bale 2018). This variant is also reported in ClinVar (Variation ID: 421483). It is found in the general population with a low overall allele frequency of 0.001% (3/251152 alleles) in the Genome Aggregation Database. The isoleucine is moderately conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Bale TA et al. Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol. 2018 Mar;28(2):183-191.
Sema4, Sema4	RCV000582520	SCV002531087	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357344	SCV001552790	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The ATM p.Ile576Val variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (rs1064795170) as “with other allele” and ClinVar (interpreted as "uncertain significance" by Invitae, GeneDx and Color). The variant was identified in control databases in 3 of 245,976 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Ashkenazi Jewish population in 3 of 9846 chromosomes (freq: 0.0003), but not in the African, Other, Latino, European, East Asian, Finnish, and South Asian populations. The p.Ile576 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000690771	SCV002083779	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-26	no assertion criteria provided	clinical testing