13-32337158-G-C

Variant names:

• chr13-32337158-G-C
• rs28897716
• NM_000059.4:c.2803G>C
• BRCA2 p.Asp935His

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4BP6_Very_Strong

The NM_000059.4(BRCA2):c.2803G>C (p.Asp935His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000911 (AC=147) in the gnomAD database across 1,613,832 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000108. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D935= (synonymous): Likely_benign (ClinVar VariationId 427457, 3 stars); p.D935E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 821827); p.D935E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 462278); p.D935G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 481503); p.D935N: Benign/Likely_benign (ClinVar VariationId 51349, 2 stars); p.D935Y: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 559998)

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:10 B:13
• Conservation: PhyloP100: 0.312
• Publications: 52 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: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000108 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).

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.2803G>C p.Asp935His	missense	Exon 11 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.2803G>C p.Asp935His	missense	Exon 11 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.2803G>C p.Asp935His	missense	Exon 11 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.2803G>Cp.Asp935His

Exon rankExon 11 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.2803G>Cp.Asp935His

Exon rankExon 11 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.2803G>Cp.Asp935His

Exon rankExon 11 of 27

missense

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.2803G>C p.Asp935His	missense	Exon 11 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.2803G>C p.Asp935His	missense	Exon 11 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.2434G>C p.Asp812His	missense	Exon 11 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.2803G>Cp.Asp935His

Exon rankExon 11 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.2803G>Cp.Asp935His

Exon rankExon 11 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.2434G>Cp.Asp812His

Exon rankExon 11 of 27

missense

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152172	Cov:32
GnomAD2 exomes	AF: 0.0000638	AC:16	Hom:	AN:250844	Cov:
GnomAD4 exome	AF: 0.0000972	AC:142	Hom:0	AN:1461542	Cov:33
GnomAD4 genome	AF: 0.0000328	AC:5	Hom:0	AN:152290	Cov:32
TOPMed (Bravo)	AF: 0.0000680	AC:18	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:344990	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000428	AC:1	Hom:0	AN:2338	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0000903 *	1	11076	0.0000569 *	1	17570
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28418	0.0000347	1	28842
Epi25(Epilepsy)	0.0000477	2	41958	0.0000598	4	66886
SCHEMA(Schizophrenia)	0.0000417	5	120036	0.0000478	9	188462

Showing 4 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
-	3	4	Breast-ovarian cancer, familial, susceptibility to, 2 (7)
-	2	2	not provided (4)
-	1	3	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	-	BRCA2-related disorder (1)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Fanconi anemia complementation group D1 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.095	N
GPN-Star LLR	N/A	-3.0
GPN-Star score	N/A	3.0
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	94/6	polymorphism
PhyloP100	Benign	0.31
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.23
Sift	Benign	0.099	T
Sift4G	Benign	0.27	T
VESM-3B	Benign	-3.2

Showing 22 of 22 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2
Splicevardb	N/A	1.0

Showing 3 of 3 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: rs28897716;

hg19: chr13-32911295;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar