rs3092829
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000051.4(ATM):c.5497-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,612,812 control chromosomes in the GnomAD database, including 710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000051.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5497-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5497-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0215 AC: 3272AN: 152194Hom.: 36 Cov.: 32
GnomAD3 exomes AF: 0.0225 AC: 5630AN: 250650Hom.: 89 AF XY: 0.0226 AC XY: 3059AN XY: 135528
GnomAD4 exome AF: 0.0283 AC: 41334AN: 1460500Hom.: 674 Cov.: 31 AF XY: 0.0280 AC XY: 20345AN XY: 726626
GnomAD4 genome ? AF: 0.0215 AC: 3271AN: 152312Hom.: 36 Cov.: 32 AF XY: 0.0208 AC XY: 1549AN XY: 74486
ClinVar
Submissions by phenotype
not specified Benign:7
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Ataxia-telangiectasia syndrome Benign:6
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Nov 22, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 08, 2018 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 02, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jan 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Oct 23, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2013 | This alteration is classified as benign based on a combination of the following: 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. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 27, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Familial cancer of breast Benign:2
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 23, 2024 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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 | - - |
Triple-negative breast carcinoma Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM c.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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 this variant meets our laboratory's criteria to be classified as benign. - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM c.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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 this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at