chr13-32338860-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000059.4(BRCA2):​c.4505A>G​(p.Gln1502Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 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. Q1502E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

BRCA2
NM_000059.4 missense

Scores

4
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.85
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_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21669546).
BP6
Variant 13-32338860-A-G is Benign according to our data. Variant chr13-32338860-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.4505A>G p.Gln1502Arg missense_variant 11/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.4505A>G p.Gln1502Arg missense_variant 11/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign: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 GeneticsApr 18, 2024The p.Q1502R variant (also known as c.4505A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4505. The glutamine at codon 1502 is replaced by arginine, an amino acid with highly similar properties. In a population-based study of Chinese women, this variant was detected in 1/645 breast cancer patients but was not seen in 342 women with benign breast disease or 319 healthy controls (Suter NM et al. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13:181-9). This variant was also identified in 1 of 1009 patients amongst a cohort of Chinese patients with a personal history of pancreatic ductal adenocarcinoma (Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 28, 2022It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in breast cancer association studies (PMIDs: 14973102 (2004) and 31825140 (2019)). Additionally, the variant has been reported both as likely deleterious (PMID: 14973102 (2004)) and as having a decreased association with disease (PMID: 31853058 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
15
DANN
Uncertain
0.99
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.57
D
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.90
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-3.1
D;D
REVEL
Benign
0.17
Sift
Uncertain
0.013
D;D
Sift4G
Uncertain
0.052
T;T
Vest4
0.32
MutPred
0.21
Gain of phosphorylation at T1499 (P = 0.1043);Gain of phosphorylation at T1499 (P = 0.1043);
MVP
0.88
MPC
0.031
ClinPred
0.20
T
GERP RS
3.4
gMVP
0.34

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: rs876660919; hg19: chr13-32912997; API