Submissions for variant NM_000051.4(ATM):c.2236T>C (p.Phe746Leu)

gnomAD frequency: 0.00001  dbSNP: rs1017383703

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804712	SCV000944634	uncertain significance	Ataxia-telangiectasia syndrome	2022-05-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 649721). 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. 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. This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 746 of the ATM protein (p.Phe746Leu).
Ambry Genetics	RCV002424867	SCV002730951	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	clinical testing	The p.F746L variant (also known as c.2236T>C), located in coding exon 13 of the ATM gene, results from a T to C substitution at nucleotide position 2236. The phenylalanine at codon 746 is replaced by leucine, an amino acid with highly similar properties. 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 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492173	SCV004240425	uncertain significance	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000804712	SCV002077176	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-21	no assertion criteria provided	clinical testing