13-32370516-G-C

Variant names:

• chr13-32370516-G-C
• rs1555287651
• NM_000059.4:c.8446G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000059.4(BRCA2):​c.8446G>C​(p.Gly2816Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.03

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8446G>C	p.Gly2816Arg	missense_variant	Exon 19 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8446G>C	p.Gly2816Arg	missense_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8077G>C	p.Gly2693Arg	missense_variant	Exon 19 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*504G>C		non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*504G>C		3_prime_UTR_variant	Exon 18 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 2816 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 22, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G2816R variant (also known as c.8446G>C), located in coding exon 18 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8446. The glycine at codon 2816 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.19	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.80
MutPred		0.72		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.90
MPC		0.17
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555287651; hg19: chr13-32944653;