NM_000059.4:c.8850G>T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). B2_Supporting

The NM_000059.4(BRCA2):c.8850G>T (p.Lys2950Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene BRCA2 is a tumor suppressor gene (CancerMine: 139 TSG, 7 oncogene, 19 driver citations). The gene BRCA2 is a cancer driver gene (CancerMine: 139 TSG, 7 oncogene, 19 driver citations). 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) 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.). 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 ACGS-UK Somatic Oncogenicity v2025

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: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

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