Submissions for variant NM_000051.4(ATM):c.5683C>T (p.His1895Tyr)

gnomAD frequency: 0.00003  dbSNP: rs766901049

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564290	SCV000665441	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.H1895Y variant (also known as c.5683C>T), located in coding exon 37 of the ATM gene, results from a C to T substitution at nucleotide position 5683. The histidine at codon 1895 is replaced by tyrosine, an amino acid with similar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628140	SCV000749033	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1895 of the ATM protein (p.His1895Tyr). This variant is present in population databases (rs766901049, gnomAD 0.007%). 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: 481200). 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. 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	RCV001560417	SCV001782829	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321676	SCV004027245	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564290	SCV004361761	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1895 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 been identified in 8/250968 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.