13-32339436-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_000059.4(BRCA2):​c.5081G>A​(p.Arg1694Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. R1694T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

2
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.355
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38090962).
BP6
Variant 13-32339436-G-A is Benign according to our data. Variant chr13-32339436-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409591.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.5081G>A p.Arg1694Lys missense_variant 11/27 ENST00000380152.8 NP_000050.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.5081G>A p.Arg1694Lys missense_variant 11/275 NM_000059.4 ENSP00000369497 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000428
AC:
1
AN:
233448
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
126536
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000380
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.95e-7
AC:
1
AN:
1439780
Hom.:
0
Cov.:
46
AF XY:
0.00
AC XY:
0
AN XY:
714144
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:
0.0000122
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 20, 2023The p.R1694K variant (also known as c.5081G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5081. The arginine at codon 1694 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not well 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. -
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). -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 2016This sequence change replaces arginine with lysine at codon 1694 of the BRCA2 protein (p.Arg1694Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The lysine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJun 25, 2021The BRCA2 c.5081G>A variant is classified as Likely Benign (BP1, BP4) The BRCA2 c.5081G>A variant is a single nucleotide change in the BRCA2 gene, which is predicted to change the amino acid arginine at position 1694 in the protein to lysine. Disease causing variants in BRCA2 are predominantly trucating variants and this variant is a missense variant (BP1). Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 409591). It has not been reported in dbSNP or HGMD. -
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 09, 2024ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.0022
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
12
DANN
Benign
0.97
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.77
D
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-1.8
N;N
REVEL
Uncertain
0.37
Sift
Benign
0.23
T;T
Sift4G
Benign
0.45
T;T
Vest4
0.33
MutPred
0.71
Gain of ubiquitination at R1694 (P = 0.0428);Gain of ubiquitination at R1694 (P = 0.0428);
MVP
0.84
MPC
0.022
ClinPred
0.082
T
GERP RS
1.9
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: rs753721331; hg19: chr13-32913573; API