Variant 13-32340384-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):c.6029T>G(p.Val2010Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2010I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: -0.272

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08078781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.6029T>G	p.Val2010Gly	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.6029T>G	p.Val2010Gly	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250814

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	This missense variant replaces valine with glycine at codon 2010 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer or prostate cancer, and has been reported in several unaffected individuals (PMID: 18779604, 24249303, 27658390, 29215753, 31214711, 32980694). In 2 large breast cancer case-control studies conducted in Japan and by the BRIDGES consortium, this variant was reported in 5/7051 female cases and 9/11241 female controls (OR=0.885632780741425 (0.2-2.9)) (PMID: 30287823), and in 2/60466 cases and 4/53461 controls (OR=0.442 (95%CI 0.081 to 2.414); p-value=0.429) (PMID: 33471991), respectively. This variant has been identified in 5/250814 chromosomes 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 24, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2022	The p.V2010G variant (also known as c.6029T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6029. The valine at codon 2010 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported as a variant of unknown significance in Korean, African American, and Japanese individuals with suspected hereditary breast cancer (Kurian A et al. J Clin Oncol. 2008 Oct; 26(29):4752-8; Haffty B et al. Ann Oncol. 2009 Oct; 20(10):1653-9; Yoon KA et al. Cancer Res Treat, 2017 Jul;49:627-634; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457; Lee JS et al. J. Med. Genet., 2018 Dec;55:794-802; Momozawa Y et al. Nat Commun, 2018 10;9:4083). However, this variant has also been reported in controls (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dong H et al. J Med Genet. 2021 08;58:565-569). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces valine with glycine at codon 2010 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast or ovarian cancer and in two individuals affected with esophageal cancer (PMID: 9133456,18779604, 24249303, 27658390, 29176636, 29215753, 31396961, 35681111). This variant has also been detected in breast, pancreatic, and prostate cancer case-control studies in which disease association could not be established (PMID: 30287823, 31214711, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_002250). This variant has been identified in 5/250814 chromosomes 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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	Observed in individuals with breast and other cancers (Inoue 1997, Kurian 2008, Haffty 2009, Lu 2015, Nakamura 2015, Yoon 2017, Momozawa 2018, So 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.6257T>G; This variant is associated with the following publications: (PMID: 29338689, 18779604, 30415210, 30287823, 9133456, 24249303, 19491284, 26689913, 27658390, 30725392, 29215753, 31131967, 31822803, 29176636) -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2010 of the BRCA2 protein (p.Val2010Gly). This variant is present in population databases (rs80358839, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer, stomach adenocarcinoma (PMID: 18779604, 19491284, 26689913, 27124784, 27658390, 29176636, 29215753, 30287823, 31907386). ClinVar contains an entry for this variant (Variation ID: 51991). 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 with a negative predictive value of 95%. 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

0.085

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.1

DANN

Benign

0.70

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.071

M_CAP

Benign

0.073

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.19

Sift

Benign

0.094

T;T

Sift4G

Benign

0.34

T;T

Vest4

0.23

MutPred

0.50

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.76

MPC

0.037

ClinPred

0.024

GERP RS

1.7

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over