13-32376769-C-A

Position:

• chr13-32376769-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000530893.7(BRCA2):​c.8363C>A​(p.Ala2788Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. A2788V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 ENST00000530893.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.22

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2297251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8732C>A	p.Ala2911Glu	missense_variant	21/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8732C>A	p.Ala2911Glu	missense_variant	21/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8363C>A	p.Ala2788Glu	missense_variant	21/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*790C>A		non_coding_transcript_exon_variant	20/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*790C>A		3_prime_UTR_variant	20/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group D1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 26, 2002

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces alanine with glutamic acid at codon 2911 of the BRCA2 protein (p.Ala2911Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 9339). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.30	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Benign	0.10	T;T
Sift4G	Benign	0.19	T;T
Vest4		0.43
MutPred		0.37		Gain of solvent accessibility (P = 9e-04);Gain of solvent accessibility (P = 9e-04);
MVP		0.84
MPC		0.10
ClinPred		0.92	D
GERP RS		4.5
gMVP		0.62

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: rs80359130; hg19: chr13-32950906;