Submissions for variant NM_000051.4(ATM):c.38G>A (p.Arg13His)

gnomAD frequency: 0.00002  dbSNP: rs778201041

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168074	SCV000218728	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 13 of the ATM protein (p.Arg13His). This variant is present in population databases (rs778201041, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 188171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics	RCV000222429	SCV000276277	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The p.R13H variant (also known as c.38G>A), located in coding exon 1 of the ATM gene, results from a G to A substitution at nucleotide position 38. The arginine at codon 13 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in breast cancer cohorts (Dutil J et al. Sci Rep, 2019 11;9:17769; Decker B et al. J Med Genet, 2017 11;54:732-741). 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.
GeneDx	RCV000254698	SCV000322154	uncertain significance	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least three individuals with breast cancer (PMID: 28779002); Reported as a variant of uncertain significance in an individual with ataxia-telangectasia who was also heterozygous for two other variants in the ATM gene plausibly explaining the phenotype (Villagaray-Pacheco N et al. (2021) Ro J Neurol. 20 (2)); This variant is associated with the following publications: (PMID: 22895193, 29445900, 31780696, 28779002, Villagaray-Pacheco2021[Case Report])
Counsyl	RCV000168074	SCV000792414	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222429	SCV001347326	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 13 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 31780696). This variant has also been reported in an individual affected with ataxia-telangiectasia who was compound heterozygous for a truncation variant in the non-sense mediated decay region and a variant impacting a canonical +2 splice site, suggesting this variant may not be disease-causing (DOI: 10.37897/RJN.2021.2.11). This variant has been identified in 4/251386 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.
Baylor Genetics	RCV003468823	SCV004209438	uncertain significance	Familial cancer of breast	2024-03-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000168074	SCV002090154	uncertain significance	Ataxia-telangiectasia syndrome	2021-01-11	no assertion criteria provided	clinical testing