17-43045812-G-T
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_007294.4(BRCA1):c.5468-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000786 in 1,613,766 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00042 ( 5 hom. )
Consequence
BRCA1
NM_007294.4 splice_polypyrimidine_tract, intron
NM_007294.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.001610
2
Clinical Significance
Conservation
PhyloP100: 0.166
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 17-43045812-G-T is Benign according to our data. Variant chr17-43045812-G-T is described in ClinVar as [Benign]. Clinvar id is 55589.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045812-G-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0043 (655/152258) while in subpopulation AFR AF= 0.0145 (601/41538). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 6 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5468-10C>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5468-10C>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00430 AC: 654AN: 152140Hom.: 6 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
654
AN:
152140
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00120 AC: 301AN: 250432Hom.: 3 AF XY: 0.000974 AC XY: 132AN XY: 135456
GnomAD3 exomes
AF:
AC:
301
AN:
250432
Hom.:
AF XY:
AC XY:
132
AN XY:
135456
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000419 AC: 613AN: 1461508Hom.: 5 Cov.: 32 AF XY: 0.000374 AC XY: 272AN XY: 727044
GnomAD4 exome
AF:
AC:
613
AN:
1461508
Hom.:
Cov.:
32
AF XY:
AC XY:
272
AN XY:
727044
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00430 AC: 655AN: 152258Hom.: 6 Cov.: 32 AF XY: 0.00438 AC XY: 326AN XY: 74450
GnomAD4 genome
?
AF:
AC:
655
AN:
152258
Hom.:
Cov.:
32
AF XY:
AC XY:
326
AN XY:
74450
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
4
AN:
3478
ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:27Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:9
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 19, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 14, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 08, 2015 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:6Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01626 (African), derived from 1000 genomes (2012-04-30). - |
Benign, criteria provided, single submitter | literature only | Counsyl | Jan 02, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 07, 2014 | - - |
Benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | 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 | curation | Sema4, Sema4 | May 21, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | BRCA1: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 c.5468-10C>A variant was identified in 3 of 4550 proband chromosomes from individuals or families with breast or ovarian cancer (frequency: 0.001); however control chromosomes were not included in these studies (Borg 2010, Tommasi 2008, Uhrhammer 2008).The 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. One functional study did not find any effect of the variant on splicing (Houdayer 2012), and in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in only 2 of 5 different programs, though this information is not predictive enough to rule out pathogenicity. The variant was also identified in HGMD, LOVD, and the BIC database (15X with unknown clinical importance), and UMD (31X as a neutral variant). In UMD the variant was identified in four samples as co-occurring a pathogenic variant (two in BRCA1 and two in BRCA2), increasing the likelihood that the variant does not have clinical importance. The variant was listed in dbSNP (ID: rs8176316) with a minor allele frequency of 0.004 (1000 Genomes Project) and an average heterozygosity of 0.007+/-0.060. Furthermore, this variant occurs at a frequency of greater than 1% in some populations of origin and is therefore classified as a polymorphism (African American alleles in the NHLBI Exome Sequencing Project (Exome Variant Server) (frequency: 0.014), HapMap-YRI (frequency: 0.018), HAPMAP-LWK (frequency: 0.017), and HAPMAP-ASW (frequency: 0.01)). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at