Submissions for variant NM_000051.4(ATM):c.3106T>C (p.Phe1036Leu)

gnomAD frequency: 0.00004  dbSNP: rs747079458

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459438	SCV000546954	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-18	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 1036 of the ATM protein (p.Phe1036Leu). This variant is present in population databases (rs747079458, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407624). 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.
Ambry Genetics	RCV000566084	SCV000660584	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.F1036L variant (also known as c.3106T>C), located in coding exon 20 of the ATM gene, results from a T to C substitution at nucleotide position 3106. The phenylalanine at codon 1036 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in a Chinese breast cancer patient (Chen B et al. Aging (Albany NY), 2020 Feb;12:3140-3155). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566084	SCV000682101	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 1036 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/251248 chromosomes 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.
Fulgent Genetics, Fulgent Genetics	RCV002481423	SCV002792237	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-04-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470427	SCV004209543	uncertain significance	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477949	SCV004220932	uncertain significance	not provided	2016-12-29	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer in multigene panel testing cohorts (PMIDs: 32885271 (2021), 32091409 (2020)). This variant has also been observed in breast cancer and control individuals in case-control studies (PMIDs: 30287823 (2018) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00049 (9/18382 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993968	SCV004813567	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3106T>C (p.Phe1036Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 273730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3106T>C has been reported in the literature as a VUS in individuals affected with metastatic castration-resistant prostate cancer or at high risk for breast cancer (e.g. Dong_2022, Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35599270, 32068069, 30287823). ClinVar contains an entry for this variant (Variation ID: 407624). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358008	SCV001553636	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Phe1036Leu variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in the following databases: dbSNP (ID: rs747079458) as "With Uncertain significance allele", ClinVar and Clinvitae (1x, uncertain significance). The variant was also identified in control databases in 9 of 246090 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 9 of 17236 chromosomes (freq: 0.0005), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was not observed in the African, other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Phe1036 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000459438	SCV002079743	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-31	no assertion criteria provided	clinical testing