Submissions for variant NM_000051.4(ATM):c.6475T>G (p.Cys2159Gly)

gnomAD frequency: 0.00009  dbSNP: rs150408832

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220825	SCV000274115	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing	The p.C2159G variant (also known as c.6475T>G), located in coding exon 44 of the ATM gene, results from a T to G substitution at nucleotide position 6475. The cysteine at codon 2159 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587154	SCV000616647	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 28122867, 23532176)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554683	SCV000622669	uncertain significance	Ataxia-telangiectasia syndrome	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2159 of the ATM protein (p.Cys2159Gly). This variant is present in population databases (rs150408832, 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: 230532). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000220825	SCV000687706	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 2159 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 8/282836 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587154	SCV000694324	uncertain significance	not provided	2015-10-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000220825	SCV002537678	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	curation
Baylor Genetics	RCV003469006	SCV004209433	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469006	SCV005084796	likely benign	Familial cancer of breast	2024-06-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000554683	SCV002084375	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-29	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483577	SCV004228529	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-05-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.