GeneBe

17-43094745-C-T

Position:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP3BP6_Very_Strong

The ENST00000478531.6(BRCA1):​c.783G>A​(p.Gln261=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA1
ENST00000478531.6 splice_region, synonymous

Scores

2

Clinical Significance

Likely benign reviewed by expert panel U:2B:1

Conservation

PhyloP100: 1.57
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.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
Variant 17-43094745-C-T is Benign according to our data. Variant chr17-43094745-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 55698.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.786G>A p.Gln262= synonymous_variant 10/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.786G>A p.Gln262= synonymous_variant 10/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249252
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134768
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458900
Hom.:
0
Cov.:
34
AF XY:
0.00000276
AC XY:
2
AN XY:
725492
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:2Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Leu235Leu variant has been previously identified in the literature in at least one family with familial breast and/or ovarian cancer (Anczuków 2008); and it is listed once in the HGMD mutation database. This variant is not listed in the dbSNP or EVS databases, and so the frequency of this variant in the general population is not known. Although the p.Leu235Leu variant does not alter the amino acid and occurs outside of the splicing consensus sequence, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 3 of 5 different programs. However, this information is not predictive enough to rule out pathogenicity. In support of the in-silico findings, using a minigene construct, Anczuków et al (2008) demonstrated that this variant favours the production of an alternatively spliced, shortened transcript over the wild-type transcript which may have an impact at the cellular level. In summary, based on the above information, this variant is classified as a variant of unknown significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 19, 2022This sequence change affects codon 262 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant is present in population databases (rs397509317, gnomAD 0.0009%). This variant has been observed in individual(s) with breast cancer (PMID: 31706072). ClinVar contains an entry for this variant (Variation ID: 55698). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Jun 29, 2017Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
CADD
Benign
18
DANN
Benign
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.55
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.55
Position offset: -1

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: rs397509317; hg19: chr17-41246762; API