Submissions for variant NM_000051.4(ATM):c.6536T>C (p.Ile2179Thr)

gnomAD frequency: 0.00001  dbSNP: rs878853532

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229363	SCV000283019	uncertain significance	Ataxia-telangiectasia syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2179 of the ATM protein (p.Ile2179Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 236754). 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 disruptive. 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	RCV000255846	SCV000322059	uncertain significance	not provided	2023-02-21	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)
Ambry Genetics	RCV000572519	SCV000660714	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-01	criteria provided, single submitter	clinical testing	The p.I2179T variant (also known as c.6536T>C), located in coding exon 44 of the ATM gene, results from a T to C substitution at nucleotide position 6536. The isoleucine at codon 2179 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000572519	SCV000682346	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2179 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 2/53459 controls (PMID: 33471991). This variant has been identified in 1/251454 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	RCV000779807	SCV000916612	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6536T>C (p.Ile2179Thr) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 1/60466 cases, but was also found in 2/53461 controls (Dorling_2021, reported through LOVD). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33471991). ClinVar contains an entry for this variant (Variation ID: 236754). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000779807	SCV002064610	uncertain significance	not specified	2019-07-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255846	SCV004033161	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP1, BP4
Baylor Genetics	RCV003463631	SCV004207758	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255846	SCV004229290	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Natera, Inc.	RCV000229363	SCV001458447	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing