GeneBe

rs143160357

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_007294.4(BRCA1):​c.-86C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 445,956 control chromosomes in the GnomAD database, including 3 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 0.00079 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -0.243
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]
NBR2 (HGNC:20691): (neighbor of BRCA1 lncRNA 2) This gene was identified by its close proximity on chromosome 17 to tumor suppressor gene BRCA1. Experimental evidence indicates that the two genes share a bi-directional promoter. Transcription for either gene is controlled individually by distinct transcriptional repressor factors. A short (112 amino acid) open reading frame is observed which includes a region derived from a LINE1 element. A strong Kozak signal is not observed for the putative ORF and the stop codon is more than 55 nucleotides upstream of the last splice site for the transcript, suggesting that the transcript is subject to nonsense-mediated decay. Therefore, this gene does not appear to encode a protein. Glucose starvation induces the expression of this gene and the long non-coding RNA transcribed by it functions with AMP-activated protein kinase in mediating the energy stress response. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 17-43125337-G-A is Benign according to our data. Variant chr17-43125337-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 323423.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr17-43125337-G-A is described in Lovd as [Likely_benign]. Variant chr17-43125337-G-A is described in Lovd as [Benign].
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.-86C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 23 ENST00000357654.9 NP_009225.1 P38398-1
BRCA1NM_007294.4 linkc.-86C>T 5_prime_UTR_variant Exon 1 of 23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.-86C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1
BRCA1ENST00000357654.9 linkc.-86C>T 5_prime_UTR_variant Exon 1 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
AF:
0.000788
AC:
120
AN:
152204
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00301
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000941
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000847
AC:
109
AN:
128622
Hom.:
0
AF XY:
0.000840
AC XY:
59
AN XY:
70240
show subpopulations
Gnomad AFR exome
AF:
0.000165
Gnomad AMR exome
AF:
0.00227
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000450
Gnomad FIN exome
AF:
0.000374
Gnomad NFE exome
AF:
0.000754
Gnomad OTH exome
AF:
0.00127
GnomAD4 exome
AF:
0.000834
AC:
245
AN:
293634
Hom.:
1
Cov.:
0
AF XY:
0.000887
AC XY:
147
AN XY:
165678
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00213
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000706
Gnomad4 FIN exome
AF:
0.000162
Gnomad4 NFE exome
AF:
0.000822
Gnomad4 OTH exome
AF:
0.000731
GnomAD4 genome
AF:
0.000788
AC:
120
AN:
152322
Hom.:
2
Cov.:
32
AF XY:
0.000967
AC XY:
72
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00301
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000941
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.000679
Hom.:
0
Bravo
AF:
0.000842
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA1: BS1, BS2 -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:2
Jun 14, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

#N/A -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Malignant tumor of breast Uncertain:1
Apr 08, 2020
Center of Medical Genetics and Primary Health Care
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

ACMG Guidelines 2015 criteria This variant is in the 5' UTR of the BRCA1 gene. This variant has been reported in a few cases in ClinVar as a VUS. 1 benign prediction from DANN versus no pathogenic predictions supports its benign effect (BP4 Benign Supporting). In our study it was detected in a 30-year-old female patient with unilateral breast cancer and no reported family history of cancer. Therefore, due to lack of sufficient evidence we classified this variant as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer Benign:1
Jun 18, 2013
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Jan 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
6.5
DANN
Benign
0.85
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs143160357; hg19: chr17-41277354; API