13-32380124-G-C

Position:

• chr13-32380124-G-C

Variant summary

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

The NM_000059.4(BRCA2):​c.9235G>C​(p.Val3079Leu) variant causes a missense change involving the alteration of a non-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. V3079I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.168

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9235G>C	p.Val3079Leu	missense_variant	24/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9235G>C	p.Val3079Leu	missense_variant	24/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8866G>C	p.Val2956Leu	missense_variant	24/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1293G>C		non_coding_transcript_exon_variant	23/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1293G>C		3_prime_UTR_variant	23/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The p.V3079L variant (also known as c.9235G>C), located in coding exon 23 of the BRCA2 gene, results from a G to C substitution at nucleotide position 9235. The valine at codon 3079 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	14
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.36	N
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.17	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.69	N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.033	D;D
Vest4		0.42
MutPred		0.64		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.91
MPC		0.071
ClinPred		0.74	D
GERP RS		3.4
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-32954261;