rs145119475
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000051.4(ATM):c.4060C>A(p.Pro1354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 1.50
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 Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.06936616).
BP6
Variant 11-108287666-C-A is Benign according to our data. Variant chr11-108287666-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127379.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=9}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.4060C>A | p.Pro1354Thr | missense_variant | 27/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.4060C>A | p.Pro1354Thr | missense_variant | 27/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes 0.000184 AC: 28AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000193 AC: 48AN: 248752Hom.: 0 AF XY: 0.000230 AC XY: 31AN XY: 134668
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GnomAD4 exome AF: 0.000183 AC: 268AN: 1461558Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116AN XY: 727072
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GnomAD4 genome 0.000184 AC: 28AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14AN XY: 74264
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 28779002, 33280026, 34299313, 20305132, 21787400, 26689913, 29522266, 30262796, 29684080, 28652578, 27913932, 31658756, 32854451, 35047863) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ATM: PM2, BP4 - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 25, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 17, 2019 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 28, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 16, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 21, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 19, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2021 | This 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.4060C>A (p.Pro1354Thr) variant has an allele frequency of 0.00018 (0.002%, 48/ 265,608 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00038 (0.04%, 44/115,626 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026). - |
not specified Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2024 | Variant summary: ATM c.4060C>A (p.Pro1354Thr) results in a non-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 0.00019 in 248752 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00019 vs 0.001), allowing no conclusion about variant significance. However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in Southern Europeans 0.0012 (14/11412 alleles), suggesting that the variant could be a benign polymorphism. In addition, the variant was reported in 6/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). c.4060C>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, but was also repeatedly found in controls or non-cancer-related patient cohorts (e.g. Tavtigian_2009, Bernstein_2010, Tavera-Tapia_2017, Tiao_2017, Quezada Urban_2018, Urbina-Jara_2019, Kraemer_2019, Fanale_2020, Dorling_2021, Guglielmi_2021, Yu_2022), providing no strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21787400, 19781682, 20305132, 26689913, 27913932, 28652578, 30262796, 31422574, 31658756, 32854451, 34299313, 35047863). ClinVar contains an entry for this variant (Variation ID: 127379). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 21, 2015 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
| 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. - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | - - |
ATM-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 27, 2023 | The ATM c.4060C>A variant is predicted to result in the amino acid substitution p.Pro1354Thr. This variant has been reported in individuals with a personal history of cancer (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12) and has also been reported in an equal numbers of breast cancer cases and controls (Tavtigian et al. 2009. Table S2. PubMed ID: 19781682). In two other large cancer cohort studies, this variant was reported as a variant of uncertain significance (Quezada Urban et al. 2018. PubMed ID: 30262796, Supplementary Table 2; Fanale et al. 2020. PubMed ID: 32854451). It has been reported at frequencies up to ~0.04% in a large population database and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127379/). Although we suspect that this variant could be benign, at this time, its clinical significance is classified as uncertain due to the absence of conclusive functional and genetic evidence. - |
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.Pro1354Thr variant was identified in a large-scale case control study in 1 of 5062 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Tavtigian-2009). The variant was identified in dbSNP (ID: rs145119475) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and University of Chicago). The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 50 of 274452 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017) including 45 of 124128 European chromosomes and 1 of 6442 “other” chromosomes. The p.Pro1354Thr residue is not conserved in mammals, the threonine amino acid is found in mouse, African clawed frog, and zebrafish; and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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 16, 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 cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
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;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;L;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;.
REVEL
Benign
Sift
Benign
T;T;T;.
Sift4G
Benign
T;T;T;T
Polyphen
0.0010
.;B;B;.
Vest4
0.25, 0.28
MVP
MPC
0.14
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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