rs147934285
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000051.4(ATM):āc.2096A>Gā(p.Glu699Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. E699Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2096A>G | p.Glu699Gly | missense_variant | 13/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2096A>G | p.Glu699Gly | missense_variant | 13/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000769 AC: 117AN: 152198Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000183 AC: 46AN: 251108Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135726
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461632Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727120
GnomAD4 genome ? AF: 0.000775 AC: 118AN: 152316Hom.: 1 Cov.: 32 AF XY: 0.000644 AC XY: 48AN XY: 74484
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 30, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2023 | Variant summary: ATM c.2096A>G (p.Glu699Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251298 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal estimated allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was also reported in 9 African American individuals in the Flossies database (with a frequency of 0.003517) who were older than 70 years of age, and never had cancer, further suggesting a benign outcome for the variant. c.2096A>G has been reported in the literature in individuals affected with breast Cancer, colorectal cancer, endometrial cancer, pancreatic ductal adenocarcinoma and two individuals being tested for Lynch syndrome (e.g. Yurgelun_2015, Ring_2016, Tung_2016, Yurgelun_2017, Pearlman_2016, Tavtigian_2009, Chaffee_2018, Eygelaar_2022). These reports however, do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=5), benign (n=1) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2014 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2014 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 01, 2020 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Glu699Gly variant was identified in 4 of 9322 proband chromosomes (frequency: 0.0004) from individuals or families with endometrial cancer, breast cancer or Lynch syndrome and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Ring 2016, Tavtigian 2009, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147934285) as "With other allele", ClinVar (classified as benign by Ambry Genetics and EGL; as likely benign by GeneDx and two other submitters; and as uncertain significance by Invitae, Integrated Genetics/Laboratory Corporation of America and Counsyl). The variant was not identified in LOVD 3.0. The variant was identified in 65 of 276878 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 51 of 24024 chromosomes (freq: 0.002), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 11 of 34400 chromosomes (freq: 0.0003), European in 2 of 126504 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu699 residue is conserved in mammals but not in more distantly related organisms, and 5 of 5 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) 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. - |
ATM-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 17, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 07, 2023 | - - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 07, 2024 | 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at