NM_000051.4:c.8734A>G
Variant summary
Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. BP2_StrongPP3
This summary comes from the ClinGen Evidence Repository: The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157198/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received -3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8734A>G | p.Arg2912Gly | missense_variant | Exon 60 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152176Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000219 AC: 55AN: 251450 AF XY: 0.000235 show subpopulations
GnomAD4 exome AF: 0.000183 AC: 267AN: 1461760Hom.: 1 Cov.: 31 AF XY: 0.000198 AC XY: 144AN XY: 727180 show subpopulations
Age Distribution
GnomAD4 genome 0.000204 AC: 31AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74464 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:7
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 24728327, 30613976, 20346647, 21787400, 12673797, 25452441, 27443514, 26976419, 28135145, 28828701, 26787654, 26483394, 28093616, 28779002, 11505391, 12810666, 17166884, 29945567, 30197789, 28652578, 31159747, 32183364, 34426522, 33280026, 33471991, 33436325, 33910496, 34573280, 35047863, 35365198, 35886069, 34761457, 35475445, 36555667, 35029067, 36983044, 34326862, 31882575, Richardson2024[Preprint], 38701358, 38734904, 34262154, 23532176, 35534704) -
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The ATM c.8734A>G; p.Arg2912Gly variant (rs376676328), is reported in the literature in individuals affected with various forms of suspected hereditary cancer and suspected immunodeficiency (selected references: Teraoka 2001, Goldgar 2011, Young 2011, and Grossi 2021). However it has also been reported in trans with a pathogenic variant in individuals without signs of ataxia-telangiectasia (ClinGen VCEP). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (50 / 129,162 alleles, including 1 homozygotes) in the Genome Aggregation Database. The arginine at codon 2912 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.88). Due to conflicting information, the clinical significance of the p.Arg2912Gly variant is uncertain at this time. REFERENCES: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP: https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2560f0e1-9f2c-47aa-bea7-48edcf90c9a7 Goldgar et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. PMID: 21787400. Grossi et al. Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes (Basel). 2021 Aug 24;12(9):1299. PMID: 34573280. Teraoka et al. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer. 2001 Aug 1;92(3):479-87. PMID: 11505391. Young et al. Pancreatic cancer as a sentinel for hereditary cancer predisposition. BMC Cancer. 2018 Jun 27;18(1):697. doi: 10.1186/s12885-018-4573-5. PMID: 29945567. -
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ATM: PP3 -
Ataxia-telangiectasia syndrome Uncertain:5
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This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2912 of the ATM protein (p.Arg2912Gly). This variant is present in population databases (rs376676328, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer and/or other cancers (PMID: 12810666, 17166884, 21787400, 27443514, 28093616, 28828701, 30814645, 34262154, 35047863, 35534704, 36983044). It has also been observed to segregate with disease in related individuals. This missense change has been observed to co-occur in individuals with a different variant in ATM that has been determined to be pathogenic (PMID: 12810666, 28828701; internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 133641). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. 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. -
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. -
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Familial cancer of breast Uncertain:4Benign:1
The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -
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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]. -
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -
Hereditary cancer-predisposing syndrome Uncertain:4Benign:1
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The c.8734A>G (p. Arg2912Gly) variant has an allele frequency of 0.00020 (0.02%, 54/268,310 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00039 (0.04%, 46/118,146 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). It is located in the PI3K domain, whose important role is highlighted by the fact that no missense variants with a minor allele frequency greater than 0.05% have been described in it (PM1_Supporting). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 + PM1_Supporting (PMID: 33280026). -
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
This missense variant replaces arginine with glycine at codon 2912 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. An experimental functional study reported that the variant may partially affect the kinase activity (PMID: 17166884). This variant has been reported in individuals affected with breast cancer (PMID: 11505391, 12673797, 12810666, 17166884, 21787400, 25452441, 26976419, 28779002, 28828701, 33471991, 35365198; DOI: 10.1186/s12859-021-04144-1), ovarian cancer (PMID: 38734904), pancreatic cancer (PMID: 26483394, 29945567), colorectal cancer (PMID: 28135145, 30814645, 35029067), prostate cancer (PMID: 32183364, 35886069), endometrial cancer (PMID: 27443514), melanoma (PMID: 36555667, 39122510), and chronic lymphocytic leukemia (PMID: 28652578). However it has also been observed in healthy individuals and controls (PMID: 21787400, 24728327, 28652578, 33471991). Breast cancer cases in the literature have been reported with pathogenic covariants in other genes (PMID: 12673797, 28828701) and with truncations in ATM (Color internal data). This variant has been identified in 58/282848 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. -
not specified Uncertain:3Other:1
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Variant summary: ATM c.8734A>G (p.Arg2912Gly) results in a non-conservative amino acid change located in the catalytic domain (IPR044107) 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 0.00029 in 253178 control chromosomes (gnomAD, Renault_2022), including 1 homozygote in the gnomAD database (of note, this individual is not included in the non-neuro dataset). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00029 vs 0.001), allowing no conclusion about variant significance. The variant has also been reported in 2/7325 European American women over the age of 70 with no personal history of cancer (FLOSSIES database). However, the variant c.8734A>G, has also been reported in the literature in numerous individuals affected with Breast and other cancer phenotypes (e.g. Bernstein_2003, Goldgar_2011, Pylkas_2007, Pylkas_2007, Ring_2016, Teraoka_2001, Thorstenson_2003, Thorstenson_2003, Young_2018, Zidan_2017, Rizzolo_2019, Tsaousis_2019, Jarhelle_2019, Rantapero_2020, Feliubadalo_2020, Karlsson_2021, Mikaeel_2022) as well as in an individual with immune deficiency (Grossi_2021). One of these reports demonstrated an incomplete co-segregation with disease, due to its presence in unaffected family members, as well as other affected family members who did not carry this variant (Pylkas_2007). In another report a co-occurrence with a pathogenic variant has been noted (BRCA1 c.68_69delAG, p.Glu23ValfsX17; Thorstenson_2003), providing supporting evidence for a benign role. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 39/60466 cases and in 30/53461 controls (Dorling_2021 through LOVD). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a partial defect in kinase activity, but normal ATM expression and protein stability, no dominant-negative effect and no increased sensitivity to irradiation (Pylkas_2007). The following publications have been ascertained in the context of this evaluation (PMID: 12673797, 25452441, 33471991, 33280026, 21787400, 34573280, 31882575, 33436325, 34761457, 17166884, 32183364, 35365198, 27443514, 30613976, 11505391, 12810666, 31159747, 29945567, 28828701). Multiple ClinVar submitters have assessed the variant since 2014 with a predominant consensus as VUS and some submitters citing overlapping evidence utilized in the context of this evaluation (VUS, n=19; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.8734A>G, in exon 60 that results in an amino acid change, p.Arg2912Gly. This sequence change has been described in the gnomAD database with a frequency of 0.039% in the European sub-population (dbSNP rs376676328). The p.Arg2912Gly change has been reported in an individual with endometrial cancer (PMID: 27443514), an individual with prostate cancer (PMID: 29945567), and families with breast cancer (PMID: 11505391, 12810666, 17166884). However, the p.Arg2912Gly change has also been observed in a family with a pathogenic BRCA1 variant (PMID: 12810666) and has shown incomplete segregation with the cancer phenotype in two breast cancer kindreds (PMID: 17166884). An in vitro functional study demonstrated that the p.Arg2912Gly change does not impact protein stability, but partially impacts ATM kinase activity (PMID: 17166884). The p.Arg2912Gly change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2912Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Arg2912Gly change remains unknown at this time. -
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1Other:1
Variant interpreted as Uncertain significance and reported on 06-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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Breast and/or ovarian cancer Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.8734A>G variant is predicted to result in the amino acid substitution p.Arg2912Gly. The Arg2912 residue, located within the kinase domain of the ATM protein, has been highly conserved during evolution. This variant has been reported with a frequency of 0.038% among European (non-Finnish) individuals of unknown phenotype (including one homozygous individual) in a large population database, and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133641/). This variant has also been reported in multiple individuals with personal or family history of breast cancer (Teraoka et al. 2001, PubMed ID: 11505391; Thorstenson et al. 2003, PubMed ID: 12810666; Goldgar et al. 2011, Table S1, PubMed ID: 21787400; Couch et al. 2015, Table S6, PubMed ID: 25452441) and colorectal cancer (Yurgelun et al. 2017, PubMed ID: 28135145). However, Pylkäs et al. has reported incomplete segregation of this variant with familial breast cancer (Pylkäs et al. 2007, PubMed ID: 17166884). These authors further functionally demonstrated that the p.Arg2912Gly variant does not impair the phosphorylation of all the ATM substrates, indicating that a dominant-negative effect is unlikely for this variant. Taken together, although there is a possibility that the p.Arg2912Gly variant may impair protein-protein interactions associated with optimal ATM activity, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -
Malignant tumor of breast Benign:1
The ATM p.Arg2912Gly variant was identified in 7 of 8092 proband chromosomes (frequency: 0.0009) from Finnish (BRCA1/2 negative), Austrian, and American individuals or families with HBOC or breast cancer and was not identified in 7520 control chromosomes from healthy and unselected individuals (Tung 2016, Thorstenson 2003, Teraoka 2001, Pylkas 2007). In one study, 1 affected individual had the variant cooccurring with a pathogenic BRCA1 mutation (185delAG, 39stop) (Thorstenson 2003). In another study, segregation of the variant with cancer was not shown as several unaffected carriers occurred in the families of both positive cases (Pylkas 2007). Additionally, functional assays using LCL (lymphblastoid cell lines) demonstrated the variant to have similar protein expression levels to wildtype, and a partial defect in the phosphorylation of ATM substrates (Pylkas 2007). The variant was also identified in dbSNP (ID: rs376676328) “With Uncertain significance allele”, ClinVar (classified as uncertain significance; submitters: Invitae, Ambry Genetics, GeneDx, Color Genomics; and classification not provided by ITMI), Clinvitae (3x), and in control databases in 61 (1 homozygous) of 277204 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: Other in 1 of 6466 chromosomes (frequency: 0.0002), Latino in 1 of 34420 chromosomes (frequency: 0.00003), European Non-Finnish in 53 (1 homozygous) of 126696 chromosomes (frequency: 0.0004), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), European Finnish in 1 of 25794 chromosomes (frequency: 0.00004), and South Asian in 1 of 30782 chromosomes (frequency: 0.00003). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD, and GeneInsight – COGR (unavailable). The p.Arg2912 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at