Submissions for variant NM_000051.4(ATM):c.4279G>A (p.Ala1427Thr)

gnomAD frequency: 0.00009  dbSNP: rs2229021

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130581	SCV000185453	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	The p.A1427T variant (also known as c.4279G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4279. The alanine at codon 1427 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This amino acid position is not well 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.
GeneDx	RCV000222514	SCV000278825	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, prostate or pancreatic cancer (Hirsch et al., 2008; Tavtigian et al., 2009; Bhai et al., 2021; Giri et al., 2022; Yu et al., 2022); This variant is associated with the following publications: (PMID: 22529920, 30197789, 19781682, 17333338, 35047863, 34326862, 35666082)
Invitae	RCV000467455	SCV000546875	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1427 of the ATM protein (p.Ala1427Thr). This variant is present in population databases (rs2229021, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, prostate cancer (PMID: 17333338, 19781682, 34326862, 35047863, 35666082). ClinVar contains an entry for this variant (Variation ID: 141884). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Counsyl	RCV000467455	SCV000792232	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000222514	SCV000859746	uncertain significance	not provided	2018-03-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130581	SCV000911024	likely benign	Hereditary cancer-predisposing syndrome	2016-06-21	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257474	SCV001434280	uncertain significance	Familial cancer of breast	2019-10-29	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with breast cancer (Hirsch 2008, Tavtigian 2009). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Genome-Nilou Lab	RCV000467455	SCV001653347	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225432	SCV002504713	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307403	SCV002600386	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4279G>A (p.Ala1427Thr) 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 2.8e-05 in 249502 control chromosomes, and in 2/2559 unaffected African American women over the age of 70 in the FLOSSIES database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4279G>A has been reported in the literature in individuals affected with Breast Cancer and Prostate Cancer without evidence of causality (Hirsch_2008, Giri_2022). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as either VUS (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001257474	SCV004015197	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	ATM (c.4279G>A) genes. These variants are missense mutations that substitute one amino acid for another. The current evidence uncertain significance category. Therefore, the diagnosis of hereditary cancer syndrome is not confirmed.
Natera, Inc.	RCV000467455	SCV002081744	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-14	no assertion criteria provided	clinical testing