13-32379413-G-T

Variant names:

• chr13-32379413-G-T
• rs11571769
• NM_000059.4:c.8851G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000059.4(BRCA2):​c.8851G>T​(p.Ala2951Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2951T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 7.91
• Publications: 76 publications found

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):

• breast-ovarian cancer, familial, susceptibility to, 2

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32379413-G-T is Benign according to our data. Variant chr13-32379413-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 441405.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8851G>T	p.Ala2951Ser	missense_variant	Exon 22 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8851G>T	p.Ala2951Ser	missense_variant	Exon 22 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8482G>T	p.Ala2828Ser	missense_variant	Exon 22 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*909G>T		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*909G>T		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Pathogenic:1

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: 2 functional domains – a nucleic acid-binding OB-fold (R2669-3184L aa), which functions as ssDNA binding and nucleic acid recognition site; and the Tower domain (M2831-2967T aa) with a major role in tumor suppression and DNA binding. Hot-spot has 29 non-VUS coding variants (16 pathogenic and 13 benign), pathogenicity = 55.2%, proximity score 6.295 > threshold 2.472. PM2 Pathogenic Moderate: Variant not found in GnomAD exomes. Variant not found in GnomAD genomes. PP3 Pathogenic Supporting: 7 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationTaster, PrimateAI and SIFT vs 2 benign predictions from MVP and REVEL. PP4 Pathogenic Supporting: Patient was diagnosd with breast cancer at the age 49 yo with strong family history of breast cancer. Therefore, this variant was classified as a Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Benign:1

May 16, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.012	D
PhyloP100		7.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.89	N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.43
MutPred		0.40		Gain of phosphorylation at A2951 (P = 0.0191);Gain of phosphorylation at A2951 (P = 0.0191);
MVP		0.87
MPC		0.16
ClinPred		0.95	D
GERP RS		5.6
gMVP		0.29
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs11571769; hg19: chr13-32953550;