Submissions for variant NM_000051.4(ATM):c.8479T>A (p.Phe2827Ile)

gnomAD frequency: 0.00001  dbSNP: rs370152402

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165657	SCV000216394	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.F2827I variant (also known as c.8479T>A), located in coding exon 57 of the ATM gene, results from a T to A substitution at nucleotide position 8479. The phenylalanine at codon 2827 is replaced by isoleucine, an amino acid with highly similar properties. In one study, a heterozygous p.F2827I cell line was compared to normal and AT cell lines, and the p.F2827I cell line showed altered radiation response and mRNA levels but similar ATM protein levels and kinase activity when compared to normal cell lines (Fernet M et al. Br. J. Cancer 2004 Feb; 90(4):866-73). 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.
GeneDx	RCV000485679	SCV000568340	uncertain significance	not provided	2016-06-02	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8479T>A at the cDNA level, p.Phe2827Ile (F2827I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTT>ATT). Functional studies demonstrated cells heterozygous for this variant showed decreased cell survival, mRNA expression levels, and increased radiosensitivity compared to wild type cells (Fernet 2004). ATM Phe2827Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Phenylalanine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Phe2827Ile occurs at a position that is conserved across species and is located in the PI3-PI4 kinase domain (Tavtigian 2009, Stracker 2013, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Phe2827Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628018	SCV000748905	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2827 of the ATM protein (p.Phe2827Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 14970866; Invitae). ClinVar contains an entry for this variant (Variation ID: 186122). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 14970866). This variant disrupts the p.Phe2827 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8755918, 9000145, 19431188, 25040471). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.