rs1800059
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.5071A>C(p.Ser1691Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,054 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 5 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 1.22
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.008389473).
BP6
Variant 11-108299779-A-C is Benign according to our data. Variant chr11-108299779-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127399.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=1, not_provided=1, Benign=10}. Variant chr11-108299779-A-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (244/152324) while in subpopulation NFE AF= 0.00238 (162/68032). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.5071A>C | p.Ser1691Arg | missense_variant | 34/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.5071A>C | p.Ser1691Arg | missense_variant | 34/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.00160 AC: 244AN: 152206Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00176 AC: 442AN: 251232Hom.: 2 AF XY: 0.00163 AC XY: 221AN XY: 135760
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GnomAD4 exome AF: 0.00205 AC: 2996AN: 1461730Hom.: 5 Cov.: 31 AF XY: 0.00193 AC XY: 1407AN XY: 727172
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GnomAD4 genome 0.00160 AC: 244AN: 152324Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:29Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1Benign:9
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 26, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jun 02, 2017 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Oct 26, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Apr 21, 2016 | - - |
| Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Benign, for Ataxia-telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:19431188). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 09, 2019 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Benign:7
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2021 | This variant is associated with the following publications: (PMID: 24728327, 11606401, 26979391, 28652578, 22420423, 22250480, 25742471, 14754616, 19431188, 9463314, 25980754, 26787654, 11505391, 27153395, 28202063, 28196074, 26933808, 28695297, 25133958, 28767289) - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 12, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | ATM: BP4, BS1 - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 17, 2023 | - - |
not specified Benign:5Other:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 19, 2017 | Variant summary: The ATM c.5071A>C (p.Ser1691Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 493/276958 control chromosomes (3 homozygotes) at a frequency of 0.001780, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant is likely a benign polymorphism. The variant has been reported in multiple breast cancer cases and cancer families, and in one ataxia-telangiectasia patient. None of the publications provide strong evidence for causality, lacking co-occurrence and co-segregation data, and often not providing the BRCA status of affected individuals. Multiple reputable clinical labs have classified this variant as likely benign/benign, without evidence to independently evaluate. Taken together, based on the prevalence in general population and by applying ACMG rules, the variant was classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 20, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 22, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:5
| Benign, criteria provided, single submitter | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.5071A>T (p.Ser1691Arg) missense variant has an allele frequency of 0.18%, (476/268,092 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.30%, (354/117,946 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 3 individuals of the gnomAD v2.1.1 non-neuro dataset (BS2_Supporting). Functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line and proper controls showed that: 1) the level of ATM protein was comparable to that of the positive control; 2) the ability of the modeled protein to phosphorylate Smc1, Nbs1, Chk2, and p53 following exposure of the cells to ionizing radiation and to autophosphorylate serine 1981 was also no different from the positive control; 3)The variant protein formed foci that colocalized with yH2AX following exposure to ionizing radiation (BS3; PMID:19431188). Therefore, this variant meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting + BS3 (PMID: 33280026). - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Nov 14, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 04, 2014 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 14, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 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. - |
Breast and/or ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 20, 2022 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Ser1691Arg variant was identified in 20 of 5886 proband chromosomes (frequency: 0.003) from American, Dutch and Lebanese individuals or families with breast cancer (high risk or familial or nonfamilial) or a history of Lynch syndrome associated cancer and/or polyps or individuals with unspecified cancer undergoing radiotherapy, and was identified in 4 of 3578 control chromosomes from healthy individuals (frequency: 0.001) (Petereit_2013_24416720, Broeks_2008_17393301, Jalkh_2017_28202063, Teraoka_2001_11505391, Bodian_2014_24728327, Yurgelun_2015_25980754 , Stredrick_2006_16652348). Functional studies using an expression construct to model ATM missense variants showed the variant’s level of ATM protein expression and kinase activity was comparable to wildtype (Barone_2009_19431188). The variant was identified in dbSNP (ID: rs1800059) “With other allele”, ClinVar (classified benign by Invitae, Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), likely benign by GeneDx, ARUP and classification not provided by ITMI), Clinvitae (3x), Cosmic (seen 2x in a malignant melanoma, 1x in a haematopoietic neoplasm and 3x in a carcinoma of the large intestine), LOVD 3.0 (1x), and was not identified MutDB. The variant was also identified in control databases in 493 (3 homozygous) of 276958 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 13 of 24030 chromosomes (freq: 0.0005), “Other” in 12 of 6458 chromosomes (freq: 0.002), Latino in 24 of 34416 chromosomes (freq: 0.0007), European Non-Finnish in 372 (2 homozygous) of 126472 chromosomes (freq: 0.003), and European Finnish in 72 (1 homozygous) of 25790 chromosomes (freq: 0.003); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1691 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; however, this information is not predictive enough to rule out 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. - |
Familial cancer of breast Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 22, 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]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at