NM_000051.4:c.2149C>T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1
The NM_000051.4(ATM):c.2149C>T(p.Arg717Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,606,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R717P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.2149C>T | p.Arg717Trp | missense_variant | Exon 14 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.2149C>T | p.Arg717Trp | missense_variant | Exon 14 of 63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.0000593 AC: 9AN: 151890Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000399 AC: 10AN: 250562 AF XY: 0.0000369 show subpopulations
GnomAD4 exome AF: 0.0000234 AC: 34AN: 1454610Hom.: 0 Cov.: 30 AF XY: 0.0000207 AC XY: 15AN XY: 723664 show subpopulations
Age Distribution
GnomAD4 genome 0.0000593 AC: 9AN: 151890Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74192 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:5
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. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 717 of the ATM protein (p.Arg717Trp). This variant is present in population databases (rs147515380, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic lymphocytic leukemia and biliary tract cancer and/or personal or family history of breast and/or ovarian cancer (PMID: 30303537, 31159747, 35451682, 36029002, 36243179). ClinVar contains an entry for this variant (Variation ID: 140879). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 36029002). 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. -
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The ATM c.2149C>T p.(Arg717Trp) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer as well as control individuals (PMID: 25186627, 30287823, 32885271). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
not provided Uncertain:5
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Observed in individuals with breast cancer, ovarian cancer, or leukemia and also in unaffected controls (PMID: 26689913, 25186627, 28652578, 30303537, 37013556, 32885271, 36200007); 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; This variant is associated with the following publications: (PMID: 30303537, 24416720, 26689913, 27994516, 12697903, 30287823, 28652578, 25186627, 31159747, 32566746, 31942411, 32980694, 36200007, 33471991, 36243179, 32885271, 31214711, 37013556, 36029002, 35451682) -
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The ATM p.Arg717Trp variant was identified in 2 of 644 proband chromosomes (frequency: 0.003) from individuals or families with lymphoma and ataxia telangiectasia (Fang 2003, Petereit 2013). The variant was also identified in dbSNP (ID:rs147515380) as with uncertain significance allele, in the ClinVar and Clinvitae databases with uncertain significance by Ambry Genetics, GeneDx, Color Genomics, Invitae, and Integrated Genetics Laboratory. The variant was further identified in the Cosmic database 2X as pathogenic in tissues derived from a Lymphoid neoplasm and a carcinoid-endocrine tumor. The variant was not identified in the 1000 Genomes Project nor was it identified in the dbSNP, COGR, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8596 European American and 1 of 4402 African American alleles. In addition, the variant was identified in control databases in 12 of 276362 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24012 chromosomes (freq: 0.0001), “Other” in 1 of 6432 chromosomes (freq: 0.0002), Latino in 2 of 34310 chromosomes (freq: 0.00006), European Non-Finnish in 4 of 126346 chromosomes (freq: 0.00003), East Asian in 1 of 18702 chromosomes (freq: 0.00005), and South Asian in 1 of 30692 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, European Finnish, populations. Although the p.Arg717 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg717Trp variant may impact the protein. 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. This variant is classified as a variant of uncertain significance. -
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Hereditary cancer-predisposing syndrome Uncertain:4
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This missense variant replaces arginine with tryptophan at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer and unaffected control individuals (PMID: 25186627, 30287823, 30303537, 31159747, 32980694, 32885271, 33471991, 36200007) and in an individual with pancreatic cancer (PMID: 27994516). In a breast cancer case-control study conducted in Japan, this variant was reported in 3/11241 female and 1/12490 male controls, and absent in 7051 female and 53 male breast cancer cases (PMID: 30287823). In a large international case-control study, this variant was reported in 3/60463 breast cancer cases and 6/53455 controls (OR=0.442, 95%CI 0.111 to 1.768, p-value=0.321; PMID: 33471991). This variant has been identified in 11/281892 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. -
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The p.R717W variant (also known as c.2149C>T), located in coding exon 13 of the ATM gene, results from a C to T substitution at nucleotide position 2149. The arginine at codon 717 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in a Caucasian cancer patient undergoing radiation therapy, 1/1197 individuals from Greece, Romania and Turkey undergoing evaluation for inherited cancer predisposition, in a colorectal cancer cohort from Macedonia, and in multiple breast cancer cohorts (Petereit DG et al. Front Oncol. 2013 Dec;3:318; Tung N et al. Cancer 2015 Jan;121(1):25-33; Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535; Staninova-Stojovska M et al. Balkan J. Med. Genet. 2019 Dec;22(2):5-16; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). In one study, this variant was reported in 3/60,466 breast cancer cases and in 6/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In studies of Japanese breast, prostate and pancreatic cancer cohorts, this alteration was not observed in patients affected with cancer but seen in multiple unaffected controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Familial cancer of breast Uncertain:2Benign:1
A variant of uncertain significance was detected in the ATM gene (c.2149C>T). This missense variant replaces arginine with tryptophan at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function and they show pathogenic computational verdict based on 9 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 3 benign predictions from BayesDel_addAF, DEOGEN2 and PrimateAI. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with pancreatic cancer (PMID: 27994516), lymphoma (PMID: 12697903), unspecified cancer (PMID: 24416720) or polyposis (PMID: 31942411). This variant has been identified in 11/281892 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. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene cause breast cancer susceptibility (OMIM 114480). -
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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]. -
Hereditary breast ovarian cancer syndrome Uncertain:2
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According to the ACMG standard criteria we chose this criterion: PM2 (supporting pathogenic): PM2 als dummy -
not specified Uncertain:1
Variant summary: ATM c.2149C>T (p.Arg717Trp) results in a non-conservative amino acid change in 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 250562 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.2149C>T has been reported in the literature in individuals affected with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Fang_2013, Petereit_2013, Girard_2019, Tsaousis_2019, Dorling_2021,), however it was also reported in several healthy controls (e.g. Momozawa_2018, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at