Submissions for variant NM_000051.4(ATM):c.8044A>C (p.Thr2682Pro)

dbSNP: rs730881320

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159656	SCV000209651	uncertain significance	not provided	2014-08-14	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8044A>C at the cDNA level, p.Thr2682Pro (T2682P) at the protein level, and results in the change of a Threonine to a Proline (ACT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2682Pro 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 Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr2682Pro occurs at a position that is highly conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Thr2682Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001027101	SCV001189607	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	The p.T2682P variant (also known as c.8044A>C), located in coding exon 54 of the ATM gene, results from an A to C substitution at nucleotide position 8044. The threonine at codon 2682 is replaced by proline, an amino acid with highly similar properties. This alteration was identified with an ATM nonsense alteration in an individual diagnosed with ataxia telangiectasia; however, the phase of these alterations was not documented (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 Nov;54:732-741). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049555	SCV001213611	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with proline at codon 2682 of the ATM protein (p.Thr2682Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ATM variant in an individual affected with ataxia-telangiectasia (PMID: 21665257). ClinVar contains an entry for this variant (Variation ID: 181893). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.