NM_007294.4:c.594-2A>C

Variant names:

• chr17-43095924-T-G
• rs80358033
• NM_007294.4:c.594-2A>C

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O2_Very_StrongO3_Supporting

The NM_007294.4(BRCA1):c.594-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The gene BRCA1 is a tumor suppressor gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The gene BRCA1 is a cancer driver gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The variant allele was found at a cumulative frequency of 0.0000584 (AC=94) in the gnomAD database across 1,609,948 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000663. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign reviewed by expert panel P:3 U:11 B:6 O:1
• Conservation: PhyloP100: 3.72
• Publications: 1 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

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

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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O2Null variant in tumour suppressor gene		Splice-site frameshift, NMD predicted, LoF disease mechanism — O2 very strong (+8); Use caution: splice variant may lead to in-frame exon skipping; Use caution: splice variant may lead to expression of a well-known alternative isoform; Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 412 citations, oncogene: 22 citations, driver: 49 citations).; Canonical ±1/2 splice-site variant in TSG. NMD predicted: true. LoF mechanism: true. Frameshift result: true. In-frame result: false. Cryptic site detected: false (offset: n/a bp, in-frame: false).
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000066 — very rare (O3 supporting [+1])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 NM_007294.4	MANE Select	c.594-2A>C	splice_acceptorintron	Intron 8 of 22	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.594-2A>C	splice_acceptorintron	Intron 8 of 23	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.594-2A>C	splice_acceptorintron	Intron 8 of 23	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 22

splice_acceptorintron

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 23

splice_acceptorintron

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 23

splice_acceptorintron

Prot: NP_001394511.1UniProt: A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.594-2A>C	splice_acceptorintron	Intron 8 of 22	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.594-2A>C	splice_acceptorintron	Intron 8 of 23	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.594-2A>C	splice_acceptorintron	Intron 8 of 22	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 22

splice_acceptorintron

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 23

splice_acceptorintron

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.594-2A>C

Exon rankIntron 8 of 22

splice_acceptorintron

Prot: ENSP00000419274.2UniProt: P38398-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152180	Cov:31
GnomAD2 exomes	AF: 0.0000360	AC:9	Hom:	AN:249876	Cov:
GnomAD4 exome	AF: 0.0000617	AC:90	Hom:0	AN:1457768	Cov:30
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152180	Cov:31
TOPMed (Bravo)	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:26	Hom:0	AN:437928	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000176	5	28420	0.0000347	1	28844
SCHEMA(Schizophrenia)	0.0000387	3	77580	0.0000144	2	139198

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	2	Hereditary breast ovarian cancer syndrome (4)
-	3	1	not specified (4)
2	-	1	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	1	1	not provided (2)
-	1	-	BRCA1-related cancer predisposition (1)
-	1	-	Breast and/or ovarian cancer (1)
1	-	-	Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 (1)
-	1	-	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.89	D
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
Mutation Taster	N/A	0/100	disease causing
PhyloP100	Uncertain	3.7
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 14 of 14 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
DS_AL_spliceai	Pathogenic	0.83	Position offset: -2
Pangolin (max)	Pathogenic	0.81
Pangolin gain	Uncertain	0.47	Position offset: 19
Pangolin loss	Pathogenic	0.81	Position offset: -2
SpliceAI score (max)	Pathogenic	0.83	Details are displayed if max score is > 0.2
Splicevardb	N/A	3.0

Showing 8 of 8 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80358033;

hg19: chr17-41247941;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar