Submissions for variant NM_000051.4(ATM):c.5240A>G (p.His1747Arg)

dbSNP: rs1555105695

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527340	SCV000622575	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-25	criteria provided, single submitter	clinical testing	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. This sequence change replaces histidine with arginine at codon 1747 of the ATM protein (p.His1747Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine.
Ambry Genetics	RCV000564169	SCV000660678	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-28	criteria provided, single submitter	clinical testing	The p.H1747R variant (also known as c.5240A>G), located in coding exon 34 of the ATM gene, results from an A to G substitution at nucleotide position 5240. The histidine at codon 1747 is replaced by arginine, an amino acid with highly similar 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	RCV000564169	SCV000912988	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1747 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 ATM-related disorders in the literature. This variant has not been identified 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.
Natera, Inc.	RCV000527340	SCV001452117	uncertain significance	Ataxia-telangiectasia syndrome	2020-04-18	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000564169	SCV002050288	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	no assertion criteria provided	clinical testing