13-32339409-C-T

Variant summary

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

The ENST00000530893.7(BRCA2):​c.4685C>T​(p.Ser1562Leu) 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). Synonymous variant affecting the same amino acid position (i.e. S1562S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

BRCA2
ENST00000530893.7 missense

Scores

1
2
13

Clinical Significance

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

Conservation

PhyloP100: 0.405
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 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=0.36053205).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.5054C>T p.Ser1685Leu missense_variant 11/27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.5054C>T p.Ser1685Leu missense_variant 11/275 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkuse as main transcriptc.4685C>T p.Ser1562Leu missense_variant 11/271 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkuse as main transcriptn.5054C>T non_coding_transcript_exon_variant 10/262 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
44
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign: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 GeneticsJun 05, 2024The p.S1685L variant (also known as c.5054C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5054. The serine at codon 1685 is replaced by leucine, an amino acid with dissimilar 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. Based on the available evidence, the clinical significance of this variant remains unclear. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 23, 2023This missense variant replaces serine with leucine at codon 1685 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 18, 2022This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1685 of the BRCA2 protein (p.Ser1685Leu). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 834293). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.032
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
16
DANN
Benign
0.92
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.17
N
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.52
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Uncertain
0.40
Sift
Benign
0.13
T;T
Sift4G
Benign
0.61
T;T
Vest4
0.33
MutPred
0.70
Loss of disorder (P = 0.0129);Loss of disorder (P = 0.0129);
MVP
0.89
MPC
0.024
ClinPred
0.17
T
GERP RS
4.9
gMVP
0.40

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: rs398122791; hg19: chr13-32913546; COSMIC: COSV101203829; API