Submissions for variant NM_000051.4(ATM):c.4375G>A (p.Gly1459Arg)

gnomAD frequency: 0.00012  dbSNP: rs145667735

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586694	SCV000149101	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with leukemia, breast cancer, and Lynch-syndrome associated cancers and/or polyps but also in healthy controls (Edvardsen et al., 2007; Tavtigian et al., 2009; Yurgelun et al., 2015; Zhang et al., 2015; Tung et al., 2016; Tiao et al., 2017; Decker et al., 2017; Dominguez-Valentin et al., 2018; Tsai et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 19781682, 26976419, 28779002, 25980754, 17623063, 29458332, 30374176, 26580448, 28652578, 33436325, 35098669, 33471991)
Ambry Genetics	RCV000115192	SCV000186391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.G1459R variant (also known as c.4375G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4375. The glycine at codon 1459 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in both breast cancer patients and healthy controls across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Edvardsen H et al. Radiat Oncol. 2007 Jul;2:25). 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 this alteration remains unclear.
Invitae	RCV000196015	SCV000254105	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1459 of the ATM protein (p.Gly1459Arg). This variant is present in population databases (rs145667735, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 17623063, 25980754, 26976419, 29458332, 30374176, 33436325). ClinVar contains an entry for this variant (Variation ID: 127387). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515274	SCV000611362	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115192	SCV000682200	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1459 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in individuals affected with breast cancer (PMID: 17623063, 26976419, 28779002, 33471991), prostate cancer (PMID: 33436325), colorectal cancer (PMID: 29458332), an individual suspected of Lynch syndrome (PMID: 25980754), and in healthy controls (PMID: 19781682, 28779002, 33471991). This variant has also been identified in 16/282612 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824608	SCV000694278	uncertain significance	not specified	2023-01-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4375G>A (p.Gly1459Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 256006 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (5.1e-05 vs 0.001), allowing no conclusion about variant significance. c.4375G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/colorectal/pediatric and other cancers (example, Edvardsen_2007, Tung_2016, Yurgelun_2015, Dominguez-Valentin_2018, Zhang_2015, Tsai_2019) but also in controls (example, Tavtigian_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 variant not specified, Tsai_2019), providing supporting evidence for a benign role. 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004549552	SCV000805561	uncertain significance	ATM-related disorder	2023-08-01	criteria provided, single submitter	clinical testing	The ATM c.4375G>A variant is predicted to result in the amino acid substitution p.Gly1459Arg. This variant has been documented in individuals with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Dominguez-Valentin et al. 2018. PubMed ID: 29458332), breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Additional File 1, Edvardsen et al. 2007. PubMed ID: 17623063), and prostate cancer (Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, Tavtigian et al. has observed this variant only in the control group in a large case-control-based study on breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160467-G-A). In ClinVar, it is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127387/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Athena Diagnostics	RCV000586694	SCV001143109	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001249852	SCV001424014	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-10-19	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM protein. This is a previously reported variant (ClinVar) that has been observed in at least one breast cancer patient (PMID 26976419), two patients being tested for Lynch syndrome (PMID 25980754), a patient with familial colorectal cancer (PMID 29458332), and one healthy control with no cancer (PMID 19781682). This variant is rare in control population datasets (gnomAD database, 16/276984 alleles, .006% overall frequency). A meta-analysis in breast cancer patients did not identify any enrichment of this variant in breast cancer cases versus healthy controls (PMID 19781682). The Gly1459 residue is not located in a known functional domain, and studies assessing the effect of this variant on ATM function are not published in the literature, to our knowledge. However, multiple in silico tools queried predict that this glycine to arginine amino acid change would be damaging. The glycine at this position is highly evolutionarily conserved across mammalian species examined. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider the significance of this variant to be uncertain.
Sema4, Sema4	RCV000115192	SCV002534690	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Baylor Genetics	RCV003460803	SCV004208099	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115192	SCV004228041	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196015	SCV001462322	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing