GeneBe

rs773655919

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007294.4(BRCA1):​c.5332+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0001227
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: -0.459
Variant links:
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
Variant 17-43051056-C-A is Benign according to our data. Variant chr17-43051056-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 491106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5332+7G>T splice_region_variant, intron_variant ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5332+7G>T splice_region_variant, intron_variant 1 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251304
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461420
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 08, 2016Variant summary: This c.5332+7G>T variant affects a non-conserved nucleotide, resulting in intronic change. Although 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing, ESEfinder predicts activation of an ESE site. This variant was found in 3/120656 control chromosomes from the broad and large populations from ExAC at a frequency of 0.0000249, which does not exceed maximal expected frequency of a pathogenic allele (0.0010005) in this gene. The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information, the lack of functional studies and a very low frequency in general population, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 16, 2022- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 03, 2022- -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.64
CADD
Benign
5.3
DANN
Benign
0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00012
dbscSNV1_RF
Benign
0.0020
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773655919; hg19: chr17-41203073; API