Submissions for variant NM_000051.4(ATM):c.8732C>T (p.Thr2911Ile)

dbSNP: rs794728018

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214902	SCV000276312	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	clinical testing	The p.T2911I pathogenic mutation (also known as c.8732C>T), located in coding exon 59 of the ATM gene, results from a C to T substitution at nucleotide position 8732. The threonine at codon 2911 is replaced by isoleucine, an amino acid with similar properties. One study detected this mutation in 1/3030 pancreatic cancer cases and 0/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This alteration has also been detected in conjunction with other pathogenic ATM mutations in individuals meeting diagnostic criteria for ataxia telangiectasia (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000486041	SCV000564673	uncertain significance	not provided	2015-01-30	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8732C>T at the cDNA level, p.Thr2911Ile (T2911I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2911Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr2911Ile occurs at a position that is moderately conserved across species and is located in PI3K/PI4K domain and the p53 interaction domain (UniProt, Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether ATM Thr2911Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537344	SCV000622845	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2911 of the ATM protein (p.Thr2911Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 28888541, 29922827; Invitae). ClinVar contains an entry for this variant (Variation ID: 199662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Color Diagnostics, LLC DBA Color Health	RCV000214902	SCV000905053	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 2911 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. This variant has been reported with co-occurring pathogenic variants in individuals affected with ataxia-telangiectasia (communication with an external laboratory; ClinVar SCV000276312.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465556	SCV002760709	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Mayo Clinic Health System - Franciscan Health care, Mayo Clinic Health System	RCV000181011	SCV000233285	uncertain significance	Breast cancer, early-onset	2014-10-09	no assertion criteria provided	clinical testing