Genetic Variant BRCA2:p.Thr2722Ala (chr13-32363366-A-G) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is . The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000059.4(BRCA2):c.8164A>G(p.Thr2722Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000661383: This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 03" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2722I) has been classified as Likely pathogenic. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 8.95

Publications

2 publications found

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

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), Ambry Genetics, Genomics England PanelApp
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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

BRCA2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000059.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

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 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000661383: This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Hu C et al. Clin Cancer Res. 2022 Sep;28(17):3742-3751). Two saturation genome editing-based studies, including a haploid cell-survival assay and a humanized mouse embryonic stem cell line assay of drug response and survival, demonstrate that this nucleotide substitution is non-functional (Huang H et al. Nature. 2025 Feb;638(8050):528-537; Sahu S et al. Nature. 2025 Feb;638(8050):538-545).; SCV001384725: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447).; SCV006310897: "Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779848, 39779857, 37713444)" (PS3 met).

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 23 uncertain in NM_000059.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32363367-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545487.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

REVEL computational evidence supports a deleterious effect, 0.827

PP5

Variant 13-32363366-A-G is Pathogenic according to our data. Variant chr13-32363366-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 479367.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	NM_000059.4	MANE Select	c.8164A>G	p.Thr2722Ala	missense	Exon 18 of 27	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.8164A>G	p.Thr2722Ala	missense	Exon 18 of 27	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.8164A>G	p.Thr2722Ala	missense	Exon 18 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8164A>G	p.Thr2722Ala	missense	Exon 18 of 27	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.8164A>G	p.Thr2722Ala	missense	Exon 18 of 27	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.7795A>G	p.Thr2599Ala	missense	Exon 18 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

BRCA2-related cancer predisposition (1)

Hereditary breast ovarian cancer syndrome (1)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.76

PhyloP100

8.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.5

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.80

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over