Submissions for variant NM_000051.4(ATM):c.4724G>A (p.Arg1575His)

gnomAD frequency: 0.00005  dbSNP: rs550552791

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587149	SCV000209740	uncertain significance	not provided	2023-12-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ATM-related and other cancers, but also in unaffected controls (PMID: 18573109, 19781682, 21933854, 23585524, 26580448, 28779002, 27978560, 29522266, 30287823, 34326862, 36200007); Published functional studies demonstrate no damaging effect: kinase activity similar to wild type (PMID: 18573109, 19431188); This variant is associated with the following publications: (PMID: 18573109, 26580448, 19781682, 23585524, 26787654, 21933854, 26689913, 27720647, 29522266, 19431188, 30287823, 27978560, 33922147, 36029002, 30613976, 28779002, 34326862, 36200007, 36243179)
Ambry Genetics	RCV000159727	SCV000215125	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.R1575H variant (also known as c.4724G>A), located in coding exon 30 of the ATM gene, results from a G to A substitution at nucleotide position 4724. The arginine at codon 1575 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals diagnosed with breast cancer and control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This alteration has also been identified in individuals diagnosed with CLL, medulloblastoma and early onset colorectal cancer (Skowronska A et al. Haematologica 2012 Jan;97:142-6; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). Functional analysis of this alteration found normal protein levels and kinase activity compared to wild type (Austen B et al. Br. J. Haematol. 2008 Sep;142(6):925-33; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). 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	RCV000204984	SCV000261090	likely benign	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159727	SCV000537529	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1575 of the ATM protein. Computational prediction suggests that this variant may not affect protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect kinase activity of ATM protein (PMID: 18573109, 19431188). This variant has been reported in individuals affected with breast cancer, chronic lymphocytic leukemia, and rectal cancer (PMID: 19781682, 23585524, 27978560, 30287823, 36200007), and in unaffected individuals (PMID: 21933854, 30287823, 34262154). This variant has been detected in a breast cancer case-control meta-analysis in 8/60458 breast cancer cases and 6/53455 controls (OR=1.179, 95%CI 0.409 to 3.398, p-value=0.796; PMID: 33471991). This variant has been identified in 16/282324 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	RCV001268973	SCV000694290	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4724G>A (p.Arg1575His) 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 5.9e-05 in 255778 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.9e-05 vs 0.001), allowing no conclusion about variant significance. c.4724G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Tavtigian_2009, Momozawa_2018, Rizzolo_2019, Bhai_2021), and in individuals with a variety of other cancers (e.g. Austen_2008, Navrkalova_2012, Pearlman_2016, Lu_2015), but also in healthy controls (e.g. Momozawa_2018, Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on ATM kinase activity (Austen_2008). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as uncertain significance and one classified it as likely benign. The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 34262154, 26689913, 30287823, 23585524, 27978560, 19781682, 26787654, 30613976, 34326862). Based on the evidence outlined above, the variant was classified as uncertain significance.
Eurofins Ntd Llc (ga)	RCV000587149	SCV000705520	uncertain significance	not provided	2017-02-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204984	SCV001264586	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Division of Medical Genetics, University of Washington	RCV001250435	SCV001424807	uncertain significance	Familial cancer of breast	2019-06-27	criteria provided, single submitter	clinical testing	The c.4724G>A variant has been reported in the literature to co-occur with the ATM c.6820G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.4724G>A variant has a combined allele frequency of 0.00006 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk.
Athena Diagnostics	RCV000587149	SCV004229240	uncertain significance	not provided	2023-01-16	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). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188)
Myriad Genetics, Inc.	RCV001250435	SCV005084029	likely benign	Familial cancer of breast	2024-05-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760405	SCV005373746	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	curation	According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: BS3 (supporting benign): Barone 2009 (& Austen et al. (2008), PMID: 18573109): stable ATP kinase activity (s. Supp. Figure S1)
Mayo Clinic Laboratories, Mayo Clinic	RCV000587149	SCV005412464	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	BS3
Natera, Inc.	RCV000204984	SCV001462338	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587149	SCV002033930	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587149	SCV002037463	uncertain significance	not provided		no assertion criteria provided	clinical testing