NM_000059.4:c.7977-1G>C

Variant names:

• chr13-32363178-G-C
• rs81002874
• NM_000059.4:c.7977-1G>C

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 25 classification points (ACMG Germline Pathogenicity v2019). PVS1PS1PS3PM2_SupportingPP5_Very_Strong

The NM_000059.4(BRCA2):c.7977-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000031 (AC=5) in the gnomAD database across 1,612,350 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.52). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000073381: Studies have shown that disruption of this splice site results in skipping of exons 17-18 and skipping of exon 18, and produces a non-functional protein and/or introduces a premature termination codon (PMID:16211554, 22006311" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:23 O:1
• Conservation: PhyloP100: 9.52
• Publications: 17 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) The product of this gene in involved in maintenance of genome stability. It is involved in double-strand break repair pathways during mitotic and meiotic homologous recombination and functions in protecting DNA replication forks. The encoded protein contains sites for interactions with PALB2 and EMSY and an N-terminal DNA binding domain. It also contains a RAD51 binding domain with multiple components. It has multiple BRC repeats, an alpha helix domain, oligonucleotide binding folds, and a tower-like domain. It has a nuclear localization signal and a phosphorylation site for cyclin-dependent kinase. The C-terminus of the protein can bind single-stranded and double-stranded DNA. The product of this gene interacts with multiple proteins, including RAD51. It is involved in recruiting RAD51 filaments to DNA double-strand break sites and also in cytoplasmic division. It also acts as a tumor suppressor. Mutations in this gene or decreased expression have been implicated in multiple tumor types, including breast, ovarian, pancreatic, prostate and other cancers. [provided by RefSeq, May 2026]

BRCA2 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  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
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 25 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Splice site frameshift, NMD predicted, LoF disease mechanism — very strong (PVS1); Splice acceptor variant predicted to cause a frameshift, triggering NMD. Loss of function is a known disease mechanism for this gene.
	PS1Same amino acid change as known pathogenic		Splice site has a more-destructive ClinVar pathogenic — strong (PS1); A more pathogenic splice-site variant at the same position has been reported in ClinVar.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000073381: Studies have shown that disruption of this splice site results in skipping of exons 17-18 and skipping of exon 18, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 16211554, 22006311; internal data).; SCV000919024: The variant allele was found at a frequency of 4e-06 in 249640 control chromosomes (gnomAD). c.7977-1G>C has been reported in the literature in several individuals affected with breast, ovarian, and prostate cancer (e.g. Edwards_2003, Walsh_2011, Snape_2012, Jimenez_2013, Pritzlaff_2017, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. 13 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 and all classified the variant as pathogenic. no; SCV004848124: This variant has been shown to cause altered splicing leading to an abnormal or absent protein (Tesoriero 2005, Fraile-Bethencourt 2017).; SCV000213004: Splicing analysis has demonstrated c.7977-1G>C results in the production of a primary transcript lacking coding exon 17 (Ambry internal data; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691).; SCV000683926: RNA studies have shown that this variant causes aberrant transcripts which skip exon 18, resulting in frameshifts and premature translation stop signals (PMID: 22006311, 28339459).; SCV004101453: RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 supporting.
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/23 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000059.4. 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
	BRCA2 NM_000059.4	MANE Select	c.7977-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.7977-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.7977-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.7977-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.7977-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.7977-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: NP_001393649.1UniProt: A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA2 ENST00000380152.8	TSL:5MANE Select	c.7977-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.7977-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.7608-1G>C	splice_acceptorintron	Intron 17 of 26	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.7977-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.7977-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.7608-1G>C

Exon rankIntron 17 of 26

splice_acceptorintron

Prot: ENSP00000499438.2UniProt: A0A590UJI7

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152072	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249640	Cov:
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1460278	Cov:31
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152072	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:36924	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48414	0.0000134	1	74516

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (7)
5	-	-	not provided (5)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Familial prostate cancer (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)
-	-	-	Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	0/100	disease causing (ClinVar)
PhyloP100	Pathogenic	9.5

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
DS_AL_spliceai	Pathogenic	0.95	Position offset: 1
Pangolin (max)	Pathogenic	0.90
Pangolin gain	Uncertain	0.37	Position offset: 22
Pangolin loss	Pathogenic	0.90	Position offset: 1
SpliceAI score (max)	Pathogenic	0.95	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: rs81002874;

hg19: chr13-32937315;

COSMIC: COSV104701362;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar