rs4988111
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2_StrongBP4BA1
This summary comes from the ClinGen Evidence Repository: The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157165/MONDO:0016419/020
Frequency
Genomes: 𝑓 0.0060 ( 12 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 11 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
18
Clinical Significance
Conservation
PhyloP100: 3.53
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.6995T>C | p.Leu2332Pro | missense_variant | 48/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.6995T>C | p.Leu2332Pro | missense_variant | 48/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.00605 AC: 920AN: 152158Hom.: 12 Cov.: 32
GnomAD3 genomes
AF:
AC:
920
AN:
152158
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00162 AC: 407AN: 251036Hom.: 7 AF XY: 0.00116 AC XY: 157AN XY: 135676
GnomAD3 exomes
AF:
AC:
407
AN:
251036
Hom.:
AF XY:
AC XY:
157
AN XY:
135676
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000598 AC: 874AN: 1461632Hom.: 11 Cov.: 30 AF XY: 0.000528 AC XY: 384AN XY: 727120
GnomAD4 exome
AF:
AC:
874
AN:
1461632
Hom.:
Cov.:
30
AF XY:
AC XY:
384
AN XY:
727120
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00604 AC: 920AN: 152276Hom.: 12 Cov.: 32 AF XY: 0.00551 AC XY: 410AN XY: 74466
GnomAD4 genome
AF:
AC:
920
AN:
152276
Hom.:
Cov.:
32
AF XY:
AC XY:
410
AN XY:
74466
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
109
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
267
Asia WGS
AF:
AC:
3
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign
Submissions summary: Benign:27Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:7Other:1
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 26, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2013 | 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. - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 21, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 01, 2016 | - - |
not provided Benign:6
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | ATM: BP4, BS1, BS2 - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 11, 2016 | - - |
| 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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 24, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 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, no assertion criteria provided | clinical testing | True Health Diagnostics | Jun 18, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 12, 2014 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 21, 2020 | - - |
Ataxia-telangiectasia syndrome Benign:3
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 07, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Benign, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Familial cancer of breast Benign:3
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Benign, reviewed by expert panel | curation | ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen | Mar 09, 2022 | The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 12, 2024 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. - |
Breast and/or ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 13, 2019 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Benign:1
| Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2022 | - - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Leu2332Pro variant was identified in 6 of 2720 proband chromosomes (frequency: 0.002) from American and Brazilian individuals or families with Lynch syndrome or sporadic breast cancer and was not identified in 200 chromosomes from healthy individuals (Yurgelun_2015_25980754 , Mangone_2015_25625042). The variant was also identified in dbSNP (ID: rs4988111) “With Likely benign, Uncertain significance allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae; likely benign by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics); and classification not provided by ITMI), Clinvitae (4x); and was not identified in GeneInsight-COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 557 (7 homozygous) of 276772 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 515 (7 homozygous) of 24026 chromosomes (freq: 0.02), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 27 of 34410 chromosomes (freq: 0.0008), European Non-Finnish in 9 of 126350 chromosomes (freq: 0.00007), Ashkenazi Jewish in 1 of 10138 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003) while not observed in the East Asian and European Finnish, populations. The p.Leu2332 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 Pro 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 this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
| 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;.
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at