chr11-108244105-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):ā€‹c.649A>Gā€‹(p.Ile217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.000010 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:3O:1

Conservation

PhyloP100: 0.219
Variant links:
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.048921376).
BP6
Variant 11-108244105-A-G is Benign according to our data. Variant chr11-108244105-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133639.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=11, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.649A>G p.Ile217Val missense_variant 6/63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.649A>G p.Ile217Val missense_variant 6/63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251194
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135784
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461504
Hom.:
0
Cov.:
34
AF XY:
0.0000110
AC XY:
8
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000474
Bravo
AF:
0.0000567
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:14Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 05, 2022The ATM c.649A>G; p.Ile217Val variant (rs547045780), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 133639). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 217 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.059). Due to limited information, the clinical significance of the p.Ile217Val variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsMar 13, 2024Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 26, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 31206626, 29659569, 24728327) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 03, 2023The ATM variant has been reported in the published literature in a reportedly healthy individual (PMID: 24728327 (2014)), as well as in two breast cancer cases in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000014 (4/282528 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Aug 18, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 07, 2022This missense variant replaces isoleucine with valine at codon 217 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 4/282528 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. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Aug 12, 2024The variant is observed in one or more well-documented healthy adults. There is a small physicochemical difference between isoleucine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene ATM has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.52. The gene ATM contains 167 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Uncertain Significance. -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 04, 2024This alteration is classified as likely 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. -
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 217 of the ATM protein (p.Ile217Val). This variant is present in population databases (rs547045780, gnomAD 0.006%). This missense change has been observed in individual(s) with prostate cancer, breast cancer (PMID: 29659569, 35451682). ClinVar contains an entry for this variant (Variation ID: 133639). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 06, 2017- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Mar 19, 2020- -
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsAug 24, 2023- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 22, 2024This 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]. -
not specified Uncertain:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 20, 2023Variant summary: ATM c.649A>G (p.Ile217Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251194 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.649A>G has been reported in the literature in individuals affected with prostate cancer or breat cancer (Paulo_2018, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification providedreference populationITMISep 19, 2013- -
ATM-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 03, 2024The ATM c.649A>G variant is predicted to result in the amino acid substitution p.Ile217Val. This variant has been reported in an individual from an ancestrally diverse genome sequencing cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). It has also been reported in individuals with a history of breast cancer (listed as g.chr11_108114832_A_G in Supplementary Table, Dorling et al. 2021. PubMed ID: 33471991), but has also been reported in control cohorts (Table S3, Weitzel et al. 2019. PubMed ID: 31206626). Multiple in silico prediction tools predict this variant to be tolerated (Table S2, Paulo et al. 2018. PubMed ID: 29659569). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133639/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsSep 11, 2024This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
7.8
DANN
Uncertain
0.98
DEOGEN2
Benign
0.069
.;T;T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.71
T;T;.
M_CAP
Benign
0.0076
T
MetaRNN
Benign
0.049
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.29
.;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.36
N;N;N
REVEL
Benign
0.059
Sift
Benign
0.13
T;T;T
Sift4G
Uncertain
0.052
T;D;D
Polyphen
0.0
.;B;B
Vest4
0.056, 0.071
MutPred
0.23
Loss of catalytic residue at I217 (P = 0.0239);Loss of catalytic residue at I217 (P = 0.0239);Loss of catalytic residue at I217 (P = 0.0239);
MVP
0.77
MPC
0.10
ClinPred
0.051
T
GERP RS
3.1
Varity_R
0.032
gMVP
0.099

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs547045780; hg19: chr11-108114832; COSMIC: COSV53744043; COSMIC: COSV53744043; API