chr17-43095923-C-A

Variant names:

• chr17-43095923-C-A
• rs757781708
• NM_007294.4:c.594-1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_007294.4(BRCA1):​c.594-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000686 in 1,458,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.67
• Publications: 3 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013769671 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of -21, new splice context is: taactagtgtttcttattAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.594-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.594-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249902 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458188 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725552

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109008

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Jan 15, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.594-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 8 of the BRCA1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, this alteration occurs at a splice junction that is located at a naturally occurring, alternatively spliced exon and, thus, the degree and effects of abnormal splicing cannot be predicted (Colombo M et al. Hum. Mol. Genet., 2014 Jul;23:3666-80). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Feb 18, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.594-1G>T, located in a canonic splicing site of the BRCA1 is predicted to alter splicing, probably causing the skipping of exon 9 (10 according BIC nomenclature) (r.594_670del). However, a BRCA1 isoform that lacks exons 8 and 9 (exons 9 and 10 according BIC nomenclature) is normally expressed in tissue (PVS1_N/A). This variant is found in 1/266943 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it has been identified in the ClinVar database (4x uncertain significance) and BRCA Exchange database (not yet reviewed), but it is not present in the LOVD database. Based on the currently available information, c.594-1G>T is classified as an uncertain significance variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -

Dec 16, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>T nucleotide substitution at the -1 position of intron 8 of the BRCA1 gene. While this variant is expected to disrupt the intron 8 splice acceptor site, another canonical splice site variant c.594-2A>C at this splice site was found not to segregate with breast or ovarian cancer (PMID: 25639900, 27008870) and it has been observed in trans with a pathogenic BRCA1 co-variant in an individual who did not have early-developmental phenotype (PMID: 26884819). The naturally-occurring and functional alternative BRCA1 transcript lacking exons 8 and 9 is thought to ameliorate canonical splice site variants in exons 8 and 9 (PMID: 19892845, 27008870). To our knowledge, functional studies have not been performed for this variant nor has it been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249902 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.594-1G>T variant in BRCA1 has not been previously reported in individuals with BRCA1-associated cancers, but has been identified in 1/14982 South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs757781708). This variant occurs in the invariant region (+/- 1,2) o f the splice consensus sequence and is predicted to cause altered splicing leadi ng to skipping of exon 9; however, a BRCA1 isoform that lacks exons 9 and 10 is normally expressed in breast tissue, suggesting that the c.594-1G>T variant may not cause disease (Tesoriero 2005, Rosenthal 2015, de la Hoya 2016, Wong-Brown 2 016). In summary, the clinical significance of the c.594-1G>T variant is uncerta in. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jun 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Studies have shown that disruption of this splice site is associated with altered splicing resulting in skipping of exon 8 and 9 (also known as exon 9 and 10). However, an in-frame BRCA1 isoform that skips exons 8 and 9 is expressed in normal blood and breast tissue, suggesting that this isoform may not be deleterious (PMID: 24569164). ClinVar contains an entry for this variant (Variation ID: 440453). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 33151324). This variant is present in population databases (rs757781708, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 8 of the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.7
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.83		Position offset: -1

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

Other links and lift over

dbSNP: rs757781708; hg19: chr17-41247940;