Submissions for variant NM_000051.4(ATM):c.7382G>A (p.Arg2461His)

gnomAD frequency: 0.00001  dbSNP: rs768461085

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199157	SCV000254144	uncertain significance	Ataxia-telangiectasia syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2461 of the ATM protein (p.Arg2461His). This variant is present in population databases (rs768461085, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 30287823, 30982232, 31214711). ClinVar contains an entry for this variant (Variation ID: 216230). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	RCV000217134	SCV000274850	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-20	criteria provided, single submitter	clinical testing	The p.R2461H variant (also known as c.7382G>A), located in coding exon 49 of the ATM gene, results from a G to A substitution at nucleotide position 7382. The arginine at codon 2461 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in cancer cohorts as well as control groups across multiple studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083;Yehia L et al. PLoS Genet, 2018 04;14:e1007352; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000217134	SCV000682412	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2461 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 performed for this variant. This variant has been observed in an individual affected with breast and prostate cancer (PMID: 30287823, 30982232, 31214711, 33471991, 34299313), but also in an unaffected controls (PMID: 30287823, 33471991). This variant has been identified in 10/251270 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.
Athena Diagnostics	RCV000710682	SCV000840960	uncertain significance	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779801	SCV000916605	uncertain significance	not specified	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7382G>A (p.Arg2461His) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 273752 control chromosomes (gnomAD, Momozawa_2018). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (4e-05 vs 0.001), allowing no conclusion about variant significance. c.7382G>A has been reported in the literature in individuals affected with Breast and Prostate Cancer (example: Momozawa_2018, Wang_2019, Momozawa_2020, Guglielmi_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
GeneDx	RCV000710682	SCV003845653	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25742471, 28779002, 28949453, 23532176, 30287823, 35186721, 34570441, 34299313, 33471991, 29684080, 31214711)
Baylor Genetics	RCV003468902	SCV004209452	uncertain significance	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000710682	SCV004222138	uncertain significance	not provided	2017-09-20	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast/ovarian cancer (PMIDs: 34570441 (2021), 34299313 (2021)), 30982232 (2019), 30287823 (2018), 28779002 (2017)), in an individual with prostate cancer (PMD: 31214711 (2020)), as well as in a healthy control (PMID: 30287823 (2018)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Molecular Genetics, Royal Melbourne Hospital	RCV003468902	SCV004812417	uncertain significance	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in ATM is predicted to replace arginine with histidine at codon 2461, p.(Arg2461His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the FAT domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (8/34,588 alleles) in the Latino/admixed American population. The prevalence of the variant in affected individuals with breast cancer and prostate cancer is not significantly increased compared with the prevalence in controls (PMID: 30287823, 30982232, 31214711, 33471991). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Natera, Inc.	RCV000199157	SCV001458469	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing