13-32326527-A-G

Variant summary

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

The NM_000059.4(BRCA2):​c.545A>G​(p.Glu182Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,880 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

4
5
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.50
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=0.363698).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.545A>G p.Glu182Gly missense_variant Exon 7 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.545A>G p.Glu182Gly missense_variant Exon 7 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.176A>G p.Glu59Gly missense_variant Exon 7 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.545A>G non_coding_transcript_exon_variant Exon 6 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461548
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727082
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
AF:
0.00000656
AC:
1
AN:
152332
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Feb 21, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.545A>G (p.Glu182Gly) variant has not been reported in individuals with BRCA2-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

May 24, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 773A>G; This variant is associated with the following publications: (PMID: 32377563, 29884841) -

not specified Uncertain:1
Aug 26, 2022
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.545A>G, in exon 7 that results in an amino acid change, p.Glu182Gly. This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders and has also not been described in the population databases such as ExAC and gnomAD (dbSNP rs786202685). The p.Glu182Gly change affects a highly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu182Gly substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Glu182Gly change remains unknown at this time. -

Hereditary cancer-predisposing syndrome Uncertain:1
Dec 08, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.E182G variant (also known as c.545A>G), located in coding exon 6 of the BRCA2 gene, results from an A to G substitution at nucleotide position 545. The glutamic acid at codon 182 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1
Sep 01, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid with glycine at codon 182 of the BRCA2 protein (p.Glu182Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. 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: 186091). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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
Pathogenic
0.73
BayesDel_addAF
Benign
0.0047
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
24
DANN
Pathogenic
1.0
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.15
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Vest4
0.46
MutPred
0.11
Loss of ubiquitination at K178 (P = 0.0288);Loss of ubiquitination at K178 (P = 0.0288);
MVP
0.92
MPC
0.17
ClinPred
0.98
D
GERP RS
5.5
gMVP
0.72

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

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

Other links and lift over

dbSNP: rs786202685; hg19: chr13-32900664; API