13-32370421-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000059.4(BRCA2):​c.8351G>T​(p.Arg2784Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2784Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA2
NM_000059.4 missense

Scores

10
4
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 9.94
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-32370421-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.8351G>T p.Arg2784Leu missense_variant Exon 19 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.8351G>T p.Arg2784Leu missense_variant Exon 19 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.7982G>T p.Arg2661Leu missense_variant Exon 19 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*409G>T non_coding_transcript_exon_variant Exon 18 of 26 2 ENSP00000506251.1 A0A7P0TAP7
BRCA2ENST00000614259.2 linkn.*409G>T 3_prime_UTR_variant Exon 18 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Jan 24, 2020
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R2784L variant (also known as c.8351G>T), located in coding exon 18 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8351. The arginine at codon 2784 is replaced by leucine, an amino acid with dissimilar properties. A close-match alteration at this same codon, p.R2784W, is considered likely pathogenic and has been identified in a Fanconi anemia patient (Personal communication). This alteration was deleterious in a homology-directed DNA repair (HDR) assay (Ambry internal data). Internal structural analysis indicates that this variant is likely to disrupt BRCA2 binding to DSS1, a protein that has been shown to stabilize BRCA2 and participate in its clinically relevant functions (Ambry internal data; Yang H et al. Science 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because variants at this codon have been identified in one or more patients with Fanconi Anemia this variant may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

May 03, 2019
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Apr 10, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1
Oct 05, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2784 of the BRCA2 protein (p.Arg2784Leu). This variant is not present in population databases (gnomAD 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: 491350). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. This variant disrupts the p.Arg2784 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16683254, 21520333, 27616075, 30032850, 34350294). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
0.76
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
0.77
D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-2.1
N;N
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Vest4
0.77
MutPred
0.84
Loss of MoRF binding (P = 0.0094);Loss of MoRF binding (P = 0.0094);
MVP
0.97
MPC
0.18
ClinPred
1.0
D
GERP RS
5.3
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs80359076; hg19: chr13-32944558; API