rs139552233
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.2932T>C(p.Ser978Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000806 in 1,613,970 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00084 ( 7 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
9
5
5
Clinical Significance
Conservation
PhyloP100: 6.40
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=0.03129506).
BP6
Variant 11-108271261-T-C is Benign according to our data. Variant chr11-108271261-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=3, Benign=10}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00044 (67/152256) while in subpopulation SAS AF= 0.00352 (17/4830). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 7 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.2932T>C | p.Ser978Pro | missense_variant | 20/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.2932T>C | p.Ser978Pro | missense_variant | 20/63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.000440 AC: 67AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000951 AC: 239AN: 251278Hom.: 2 AF XY: 0.00124 AC XY: 169AN XY: 135814
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GnomAD4 exome AF: 0.000844 AC: 1234AN: 1461714Hom.: 7 Cov.: 36 AF XY: 0.000945 AC XY: 687AN XY: 727166
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GnomAD4 genome 0.000440 AC: 67AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74454
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:20
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5Benign:5
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 29, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 18, 2019 | - - |
| Uncertain significance, 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: BS1 - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Ataxia-telangiectasia syndrome Uncertain:2Benign:5
| Benign, criteria provided, single submitter | clinical testing | Dr.Nikuei Genetic Center | Jul 10, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Aug 17, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 09, 2020 | - - |
not specified Uncertain:1Benign:4
| Benign, criteria provided, single submitter | clinical testing | GeneDx | May 17, 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, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 26, 2021 | Variant summary: ATM c.2932T>C (p.Ser978Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 266408 control chromosomes, predominantly at a frequency of 0.0049 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Furthermore, it has also been reported among five individuals who are cancer free at age 70 in the FLOSSIES database. This variant has been reported in multiple affected individuals with classical AT, classical Hodgkins lymphoma, B-NHL, BrC, CRC etc. Among them the one patient with classical AT also carried another ATM variant c.8395-8404del10, and no residual ATM activity was detected via western blot in this patient sample and only about 10% expressed ATM protein detected compared to WT (Carney_2012). However, the possibility of an undetected second variant causing AT in this patient cannot be ruled out. A study evaluating the Rate Ratio of asynchronous contralateral breast cancer associated with ATM gene mutation carrier status found a non-statistically significant risk of contralateral breast cancer for missense variants in the ATM gene (RR 1.2, 95% CI = 0.8 to 1.7) (Bernstein_2010). This low RR and a 95% CI overlapping 1.0 indicate very little confidence in the assertion of association with breast cancer. Subsequently, this variant has been reported in cases and in controls by other studies (example, Dorling_2021). Multiple ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4), likely benign (n=4) and benign (n=5). Based on the evidence outlined above, and the emerging peer consensus, the variant was classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 22, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 24, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2017 | 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 | curation | Sema4, Sema4 | Jun 01, 2021 | - - |
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 | Jun 05, 2023 | - - |
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.Ser978Pro variant was identified in 10 of 9598 proband chromosomes (frequency: 0.001) from individuals or families with HBOC, Hereditary Diffuse Gastric Cancer (HDGC), Non-Hodgkin’s lymphoma, Ataxia Telangiectasia (AT), or high risk cancer, and was not identified in 168 control chromosomes from healthy individuals (Yurgelun 2015, Caminsky 2016, Castera 2014, Hansford 2015, Maxwell 2016, Bernstein 2010, Gumy Pause 2006, Carney 2012). The variant co-occurred with an ATM variant (c.8395_8404del) in an AT patient whose residual ATM protein expression level was found to be 10% (Carney 2012). The variant was also identified in dbSNP (ID: rs139552233) “With other allele” and ClinVar (classified as benign by GeneDx, Invitae and Ambry Genetics; as likely benign by EGL Genetic Diagnostics and Counsyl; and as uncertain significance by Praxis fuer Humangentik Tuebingen and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 248 of 277020 chromosomes (2 homozygous) at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 154 (2 homozygous) of 30778 chromosomes (freq: 0.005), Other in 6 of 6456 chromosomes (freq: 0.0009), Latino in 4 of 34408 chromosomes (freq: 0.0001), and European Non-Finnish in 84 of 126608 chromosomes (freq: 0.0007), while it was not observed in the African, Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser978Pro is located in the ß-adaptin binding domain and the p.Ser978 residue is conserved across mammals and other organisms; 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
Familial cancer of breast Benign:1
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 10, 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]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.94, 0.94
MVP
MPC
0.52
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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