Submissions for variant NM_000051.4(ATM):c.3793T>C (p.Phe1265Leu)

gnomAD frequency: 0.00007  dbSNP: rs371526361

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167365	SCV000218217	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.F1265L variant (also known as c.3793T>C), located in coding exon 25 of the ATM gene, results from a T to C substitution at nucleotide position 3793. The phenylalanine at codon 1265 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (George SHL et al. JAMA Netw Open, 2021 03;4:e210307). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205586	SCV000259901	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1265 of the ATM protein (p.Phe1265Leu). This variant is present in population databases (rs371526361, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 33646313). ClinVar contains an entry for this variant (Variation ID: 187620). 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 tolerated. 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.
GeneDx	RCV000483445	SCV000567223	uncertain significance	not provided	2024-02-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast or ovarian cancer (PMID: 33646313); This variant is associated with the following publications: (PMID: 33646313)
Color Diagnostics, LLC DBA Color Health	RCV000167365	SCV000913928	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780912	SCV000918558	uncertain significance	not specified	2018-08-31	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3793T>C (p.Phe1265Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276924 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3793T>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV004567344	SCV005056942	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000205586	SCV001466197	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-14	no assertion criteria provided	clinical testing