13-32379412-G-T

Variant names:

• chr13-32379412-G-T
• rs28897754
• NM_000059.4:c.8850G>T
• BRCA2 p.Lys2950Asn

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). BS2BP6_Strong

The NM_000059.4(BRCA2):c.8850G>T (p.Lys2950Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000814 (AC=1,314) in the gnomAD database across 1,613,836 control chromosomes, including 3 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00226. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K2950E: Uncertain_significance (ClinVar VariationId 2428161, 1 star); p.K2950= (synonymous): Likely_benign (ClinVar VariationId 136571, 3 stars); p.K2950N: Benign/Likely_benign (ClinVar VariationId 1169136, 2 stars); p.K2950R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 233050); p.K2950T: Likely_benign (ClinVar VariationId 822764, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:30 O:1
• Conservation: PhyloP100: 2.06
• Publications: 20 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
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (23/25 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 3.; Very high cumulative gnomAD AC = 1314 (any gene).

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.8850G>T p.Lys2950Asn	missense	Exon 22 of 27	Prot: NP_000050.3 UniProt:
	BRCA2 NM_001432077.1		c.8850G>T p.Lys2950Asn	missense	Exon 22 of 27	Prot: NP_001419006.1 UniProt:
	BRCA2 NM_001406720.1		c.8850G>T p.Lys2950Asn	missense	Exon 22 of 27	Prot: NP_001393649.1 UniProt:

BRCA2 NM_000059.4

MANE Select

HGVSc / HGVSpc.8850G>Tp.Lys2950Asn

Exon rankExon 22 of 27

missense

Prot: NP_000050.3UniProt: A0A7P0T9D7P51587

BRCA2 NM_001432077.1

HGVSc / HGVSpc.8850G>Tp.Lys2950Asn

Exon rankExon 22 of 27

missense

Prot: NP_001419006.1UniProt: A0A7P0T9D7P51587

BRCA2 NM_001406720.1

HGVSc / HGVSpc.8850G>Tp.Lys2950Asn

Exon rankExon 22 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.8850G>T p.Lys2950Asn	missense	Exon 22 of 27	Prot: ENSP00000369497.3 UniProt:
	BRCA2 ENST00000544455.6	TSL:1	c.8850G>T p.Lys2950Asn	missense	Exon 22 of 27	Prot: ENSP00000439902.1 UniProt:
	BRCA2 ENST00000530893.7	TSL:1	c.8481G>T p.Lys2827Asn	missense	Exon 22 of 27	Prot: ENSP00000499438.2 UniProt:

BRCA2 ENST00000380152.8

TSL:5MANE Select

HGVSc / HGVSpc.8850G>Tp.Lys2950Asn

Exon rankExon 22 of 27

missense

Prot: ENSP00000369497.3UniProt: P51587

BRCA2 ENST00000544455.6

TSL:1

HGVSc / HGVSpc.8850G>Tp.Lys2950Asn

Exon rankExon 22 of 27

missense

Prot: ENSP00000439902.1UniProt: P51587

BRCA2 ENST00000530893.7

TSL:1

HGVSc / HGVSpc.8481G>Tp.Lys2827Asn

Exon rankExon 22 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: 0.000756	AC:115	Hom:3	AN:152202	Cov:32
GnomAD2 exomes	AF: 0.000738	AC:185	Hom:	AN:250752	Cov:
GnomAD4 exome	AF: 0.000820	AC:1199	Hom:0	AN:1461516	Cov:31
GnomAD4 genome	AF: 0.000755	AC:115	Hom:3	AN:152320	Cov:32
TOPMed (Bravo)	AF: 0.00101	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000831	AC:406	Hom:0	AN:488604	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000854	AC:2	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000538	AC:7	Hom:	AN:13006	Cov:
UK10K	AF: 0.00106	AC:8	Hom:	AN:7562	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000543 *	6	11048	0.000968 *	17	17570
BipEx(Bipolar disorder (including schizoaffective))	0.000633	18	28418	0.000693	20	28840
Epi25(Epilepsy)	0.000787	33	41956	0.000762	51	66886
SCHEMA(Schizophrenia)	0.000530	60	113172	0.000593	113	190692

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
-	1	8	not specified (10)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	not provided (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	BRCA2-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Fanconi anemia complementation group D1 (1)
-	-	1	Inherited ovarian cancer (without breast cancer) (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.0088
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.86	D
FuncVEP CTI	Benign	0.0019
GPN-Star LLR	N/A	-5.8
GPN-Star score	N/A	5.8
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.35	T
Mutation Taster	N/A	71/29	polymorphism
PhyloP100	Benign	2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
VESM-3B	Benign	-7.3

Showing 23 of 23 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

Showing 2 of 2 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.

1 normal

1 normal (RUO)

1 no calibration

3 assays found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

Research-use-only (RUO) calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

No calibration: 1 assay (score only).

RUO results are not validated; give them no weight next to the clinical ones.

Nucleotide level

Scores from arrayed screen of BRCA2 homology directed repair function in VC-8 cells

Arrayed screen of BRCA2 homology directed repair function in VC-8 cells

• Gene: BRCA2
• Assay type: Reporter
• Mechanism: DNA repair and Double-strand break repair via homologous recombination
• Model system: Other (Cricetulus griseus)
• Score: 5.41 · p.Lys2950Asn (assay numbering)

Classified as

BS3 strongFunctionally normalIGVF Coding Variant Focus Group -- Controls: All Variants: Functionally normal

+3 more calibrations

BS3 moderateFunctionally normalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Functionally normal

BS3 very strongFunctionally normalRUO ExCALIBR calibration: BS3 Very Strong (-8)

BS3 supportingFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Supporting (-1)

Nucleotide level

Scores from sGE of BRCA2 exons 15–26 in humanized mouse embryonic stem cells

SGE of BRCA2 exons 15–26 in humanized mouse embryonic stem cells

• Gene: BRCA2
• Score: 0.312

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

BS3 moderate plusFunctionally normalRUO ExCALIBR calibration: BS3 Moderate+ (-3)

+1 more calibration

BS3 moderate plusFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Moderate+ (-3)

Nucleotide level

Scores from sGE of BRCA2 exons 15 to 26 in Hap1 cells

SGE of BRCA2 exons 15 to 26 in Hap1 cells

• Gene: BRCA2
• Score: 0.121

No calibration data

This score is at approximately the 55th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs28897754;

hg19: chr13-32953549;

COSMIC: COSV66455693;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar