chr13-32326551-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000059.4(BRCA2):​c.569C>T​(p.Pro190Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P190A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

BRCA2
NM_000059.4 missense

Scores

8
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.30
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 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000059.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-32326550-CCT-CAACG is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.3506444).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.569C>T p.Pro190Leu 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.569C>T p.Pro190Leu missense_variant Exon 7 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.200C>T p.Pro67Leu missense_variant Exon 7 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.569C>T non_coding_transcript_exon_variant Exon 6 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Aug 30, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P190L variant (also known as c.569C>T), located in coding exon 6 of the BRCA2 gene, results from a C to T substitution at nucleotide position 569. The proline at codon 190 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast and/or ovarian cancer (Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42). 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1
Jun 28, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: 219761). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24010542). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 190 of the BRCA2 protein (p.Pro190Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.0071
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.35
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.20
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Vest4
0.35
MutPred
0.30
Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);
MVP
0.91
MPC
0.15
ClinPred
0.98
D
GERP RS
5.5
gMVP
0.59

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: rs864622238; hg19: chr13-32900688; API