13-32379413-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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 Uncertain significance (★). 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: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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	n.*909G>T		3_prime_UTR_variant	Exon 21 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain: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 Uncertain:1

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2951S variant (also known as c.8851G>T), located in coding exon 21 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8851. The alanine at codon 2951 is replaced by serine, an amino acid with similar properties. This alteration was detected in 1/76 individuals of Armenian descent either with a personal and/or family history of cancer or breast. This patient was diagnosed with breast cancer at age 49 and had a family history of breast cancer in multiple relatives (Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11571769; hg19: chr13-32953550;