Submissions for variant NM_000051.4(ATM):c.3739T>A (p.Phe1247Ile)

dbSNP: rs886506379

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000776764	SCV000912408	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 1247 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 not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051970	SCV001216155	uncertain significance	Ataxia-telangiectasia syndrome	2022-06-25	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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. ClinVar contains an entry for this variant (Variation ID: 630768). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1247 of the ATM protein (p.Phe1247Ile).
Ambry Genetics	RCV000776764	SCV002621213	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-24	criteria provided, single submitter	clinical testing	The p.F1247I variant (also known as c.3739T>A), located in coding exon 24 of the ATM gene, results from a T to A substitution at nucleotide position 3739. The phenylalanine at codon 1247 is replaced by isoleucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6472 samples (12944 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. 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 p.F1247I remains unclear.