rs2227922
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.1810C>T(p.Pro604Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,608,310 control chromosomes in the GnomAD database, including 28 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 0.0041 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 26 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 4.58
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=0.0075432956).
BP6
Variant 11-108252824-C-T is Benign according to our data. Variant chr11-108252824-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127343.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=2, Benign=19, Uncertain_significance=3}. Variant chr11-108252824-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00415 (631/152128) while in subpopulation AFR AF= 0.00701 (291/41520). AF 95% confidence interval is 0.00635. There are 2 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1810C>T | p.Pro604Ser | missense_variant | 12/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.1810C>T | p.Pro604Ser | missense_variant | 12/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes 0.00415 AC: 631AN: 152010Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00319 AC: 799AN: 250226Hom.: 14 AF XY: 0.00306 AC XY: 414AN XY: 135278
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GnomAD4 exome AF: 0.00205 AC: 2978AN: 1456182Hom.: 26 Cov.: 30 AF XY: 0.00214 AC XY: 1552AN XY: 724746
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GnomAD4 genome 0.00415 AC: 631AN: 152128Hom.: 2 Cov.: 32 AF XY: 0.00403 AC XY: 300AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:33Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:8Other: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 | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jan 06, 2020 | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 07, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | May 26, 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 | Clinical Genetics, Academic Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 07, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 15, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 14, 2018 | - - |
Ataxia-telangiectasia syndrome Uncertain:2Benign:6
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jun 28, 2016 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Jul 11, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jun 16, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Benign:7Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely benign and reported on 12-22-2014 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2016 | Variant summary: The ATM variant, c.1810C>T (p.Pro604Ser) causes a missense change involving a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 345/111640 (1/323 including 5 homozygotes), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic ATM variant of 1/2000 for Breast Cancer. Therefore, suggesting the variant is a common polymorphism. The variant of interest has been reported in multiple affected individuals via publications with varying phenotypes (BrC, Lynch syndrome, B-CLL, PrC, lymphoma, Hodgkin's disease), including one individual dx with A-T that harbored this variant and another ATM variant, c.6482G>C (p.Arg2161Pro - not yet scored) and was indicated to have absent ATM protein. Two internal LCA samples (adult patients with unknown phenotypes) carried c.1810C>T variant with another pathogenic variants: 1 with a BRIP1 variant, c.440dupA (Tyr147X - classified likely pathogenic) and 1 with an ATM variant, c.1027_1030delGAAA (p.Glu343fsX2 - classified pathogenic). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available information into consideration for the phenotype of Breast Cancer, the variant of interest is classified as Benign. - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | ATM: BP4, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary cancer-predisposing syndrome Benign:5
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 10, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2019 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.1810C>T (p.Pro604Ser) missense variant has an allele frequency of 0.32%, (895/281,544 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.65%, (153/23,556 alleles) in the African subpopulation (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (+BS2_Supporting) (PMID: 33280026). - |
| Benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 15, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 30, 2020 | - - |
Familial cancer of breast Benign:3
| Benign, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 08, 2018 | This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 01, 2024 | This variant is considered 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
| Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | research | Molecular Oncology Research Center, Barretos Cancer Hospital | Aug 01, 2020 | - - |
Breast and/or ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 07, 2019 | - - |
ATM-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 20, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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.Pro604Ser variant was identified in 12 of 2910 proband chromosomes (frequency: 0.0041) from individuals or families with breast cancer, ovarian cancer, Ataxia Telangiectasia and several types of lymphomas and was present in 8 of 900 control chromosomes (frequency: 0.009) from healthy individuals (Broeks 2008, Dork 2001, Fang 2003, Gronbaek 2002, Verhagen 2011). The variant was also identified in dbSBP (ID: rs2227922) as “With Likely benign allele”, ClinVar (as likely benign by EGL Diagnostics, Genetic Services Laboratory Chicago, and GeneDx, and as benign by Invitae, Ambry Genetics and Color Genomics), Clinvitae (4x as benign and likely benign), and Cosmic (8x) databases. The variant was not identified in MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 887 of 275954 chromosomes at a frequency of 0.003214 in the following populations: Ashkenazi Jewish in 332 (10 homozygous) of 10120 chromosomes (freq. 0.0328), Other in 49 (3 homozygous) of 6424 chromosomes (freq. 0.0076), African in 161 of 23966 chromosomes (freq. 0.0067), Latino in 135 (1 homozygous) of 34286 chromosomes (freq. 0.0039), European (Non-Finnish) in 191 of 126004 chromosomes (freq. 0.0015), South Asian in 16 (1 homozygous) of 30606 chromosomes (freq. 0.0005), and European (Finnish) in 3 of 25730 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A study of Hodgkin’s lymphoma patients postulated that the p.Pro604Ser variant creates a new glycosylation site which might interfere with ATM function and protein–protein interaction (Offit 2002). The p.Pro604Ser variant was found to co-occur with p.Phe1463Cys in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). The p.Pro604 residue is conserved in in mammals but not in more distantly related organisms, and the variant amino acid Serine (Ser) is present in the African tree frog, increasing the likelihood that this variant does not have clinical significance. 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 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.64
.;P;P
Vest4
0.68, 0.85
MVP
MPC
0.33
ClinPred
T
GERP RS
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