11-108251973-T-C
Position:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.1744T>C(p.Phe582Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,613,800 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00081 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00080 ( 10 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 0.131
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0050537884).
BP6
Variant 11-108251973-T-C is Benign according to our data. Variant chr11-108251973-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127342.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=14, not_provided=1}. Variant chr11-108251973-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000805 (1176/1461450) while in subpopulation MID AF= 0.0229 (131/5714). AF 95% confidence interval is 0.0197. There are 10 homozygotes in gnomad4_exome. There are 681 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 10 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1744T>C | p.Phe582Leu | missense_variant | 11/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.1744T>C | p.Phe582Leu | missense_variant | 11/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes 0.000821 AC: 125AN: 152232Hom.: 1 Cov.: 32
GnomAD3 genomes
AF:
AC:
125
AN:
152232
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: 0.000980 AC: 246AN: 251018Hom.: 1 AF XY: 0.00115 AC XY: 156AN XY: 135702
GnomAD3 exomes
AF:
AC:
246
AN:
251018
Hom.:
AF XY:
AC XY:
156
AN XY:
135702
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: 0.000805 AC: 1176AN: 1461450Hom.: 10 Cov.: 31 AF XY: 0.000937 AC XY: 681AN XY: 727034
GnomAD4 exome
AF:
AC:
1176
AN:
1461450
Hom.:
Cov.:
31
AF XY:
AC XY:
681
AN XY:
727034
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 0.000807 AC: 123AN: 152350Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66AN XY: 74508
GnomAD4 genome
AF:
AC:
123
AN:
152350
Hom.:
Cov.:
32
AF XY:
AC XY:
66
AN XY:
74508
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:
TwinsUK
AF:
AC:
3
ALSPAC
AF:
AC:
3
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
8
ExAC
AF:
AC:
119
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:30Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:8
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 13, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 21, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2017 | Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and aromatic Phenylalanine (F) with a medium size and hydrophobic Leucine (L). 4/4 in silico tools predict the variant to be neutral. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.098% which does not exceed the maximal expected allele frequency of a disease causing AT allele (0.4%). The variant was reported in CLL, ALL and breast cancer patients, however without information about family history and co-segregation, therefore these reports do not provide strong evidence for a casual impact of the variant. It was reported as a germline alteration in a patient with T-ALL associated with a t(11:14) translocation by cytogenetic analysis with no evidence of an allelic loss in tumor DNA. One publication suggest the variant to confer a risk for CLL (OR:11.23) based on a case control study, however, the significance of this finding is uncertain due to the OR being calculated based on only one affected patient (Rudd_Blood_2006). In other studies, reporting an OR for association with sporadic T-ALL, the 95% CI's overlapped 1.0, and had very small sample sizes, thereby providing little to no confidence in the assertion of the assertion. On study reported the variant to result in normal ATM protein levels, normal kinase activity, and corrected radiosensitivity when expressed in A-T cells indicating neutrality. At least three publications (Mitui_Hum Mut_2009, Magliozzi_DiseaseMarkers_2006, Maxwell_AJHG_2016) and several clinical diagnostic laboratories classify this variant as Benign/Likely Benign. Considering all evidence, the variant was classified as Likely Benign until more information becomes available. - |
| 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, Academic Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | ATM: BP4 - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:6
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 30, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 18, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
not specified Benign:6Other:1
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 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. - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, 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 | Genetic Services Laboratory, University of Chicago | Jan 27, 2017 | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 20, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Hereditary cancer-predisposing syndrome Benign:5
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2015 | - - |
| Benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 27, 2021 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 18, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 20, 2018 | - - |
Malignant tumor of breast Benign:2
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Phe582Leu variant was identified in 3 of 3466 proband chromosomes (frequency: 0.0009) from individuals or families tested for Lynch Syndrome and with breast cancer (Johnson_2007, Yurgelun_2015). The variant was also identified in the following databases: dbSNP (ID: rs2235006) as “With Likely benign allele”, ClinVar (reported 7x, as benign by Invitae, Ambry Genetics, as likely benign by EGL Genetics, PreventionGenetics, University of Chicago, GeneDx, and ITMI without any pathogenicity predictions), Clinvitae (4x, as benign and likely benign by ClinVar, Invitae, EmvClass) and LOVD 3.0 (2x as "Probably does not affect function" prediction). The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 257 of 276854 chromosomes (1 homozygous) at a frequency of 0.0009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.000042), Other in 11 of 6454 chromosomes (freq: 0.002), Latino in 46 of 34400 chromosomes (freq: 0.0013), European Non-Finnish in 132 of 126444 chromosomes (freq: 0.001), Ashkenazi Jewish in 11 of 10148 chromosomes (freq: 0.001), and South Asian in 56 of 30774 chromosomes (freq: 0.002); it was not in the East Asian, or European Finnish populations. Constructs of the ATM c.1744T>C variant were utilized as a control in an A-T cells transfection study (Mitui_2009). The aim of the experiment was to identify site-directed mutagenesis for distinguishing polymorphisms from mutations in the ATM gene. The study demonstrated that transfecting A-T cells (AT7LA) with constructs of ATM, c.1744T>C variant yielded normal ATM protein levels, normal kinase activity, and corrected radiosensitivity, supporting classification of this variant as likely benign. The p.Phe582 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
| Benign, no assertion criteria provided | clinical testing | Center of Medical Genetics and Primary Health Care | - | - - |
Familial cancer of breast Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 01, 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]. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 22, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;N
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.0
.;B;B
Vest4
0.079, 0.20
MutPred
Loss of ubiquitination at K578 (P = 0.1151);Loss of ubiquitination at K578 (P = 0.1151);Loss of ubiquitination at K578 (P = 0.1151);
MVP
MPC
0.14
ClinPred
T
GERP RS
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