13-32340969-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000059.4(BRCA2):ā€‹c.6614T>Gā€‹(p.Val2205Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V2205M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
5
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.706
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2684672).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.6614T>G p.Val2205Gly missense_variant 11/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.6614T>G p.Val2205Gly missense_variant 11/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1456496
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
724144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submittercurationUniversity of Washington Department of Laboratory Medicine, University of WashingtonMar 23, 2023Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 04, 2023The p.V2205G variant (also known as c.6614T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6614. The valine at codon 2205 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in multiple individuals diagnosed with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Bisgin A et al. Breast J, 2019 Sep;25:1029-1033; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). 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. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 05, 2019- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 27, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 15, 2014This variant is denoted BRCA2 c.6614T>G at the cDNA level, p.Val2205Gly (V2205G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val2205Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Glycine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2205Gly occurs at a position that is moderately conserved across species and is not located in a known functional domain. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Val2205Gly is pathogenic or benign. We consider it to be a variant of uncertain significance. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 01, 2021Variant summary: BRCA2 c.6614T>G (p.Val2205Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6614T>G has been reported in the literature in individuals affected with breast cancer undergoing multigene panel testing as well as in unaffected controls (example, Tung_2015, Momozawa_2018, Bisgin_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 23, 2023This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2205 of the BRCA2 protein (p.Val2205Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 31228304). ClinVar contains an entry for this variant (Variation ID: 182229). 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
0.11
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
20
DANN
Uncertain
0.99
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.092
N
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.52
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.8
N;N
REVEL
Uncertain
0.53
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.27
T;T
Vest4
0.30
MutPred
0.33
Gain of disorder (P = 0.0287);Gain of disorder (P = 0.0287);
MVP
0.92
MPC
0.084
ClinPred
0.82
D
GERP RS
4.2
gMVP
0.15

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.

Other links and lift over

dbSNP: rs730881546; hg19: chr13-32915106; API