13-32337618-C-T

Variant names:

Variant summary

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

The NM_000059.4(BRCA2):c.3263C>T(p.Pro1088Leu) 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. P1088S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.506

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]

BRCA2 links:

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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=0.24980435).

BP6

Variant 13-32337618-C-T is Benign according to our data. Variant chr13-32337618-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.2894C>T	p.Pro965Leu	missense_variant	Exon 11 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

232856

Hom.:

AF XY:

0.00000795

AC XY:

AN XY:

125808

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000927

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Jun 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 1088 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 been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002990). This variant has been identified in 1/232856 chromosomes 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. -

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1088L variant (also known as c.3263C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3263. The proline at codon 1088 is replaced by leucine, an amino acid with similar properties. This amino acid position is 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. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Feb 04, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1_strong c.3263C>T, located in exon 11 of the BRCA2 gene, is predicted to result in the substitution of Proline by Leucine at codon 1088, p.(Pro1088Leu). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). This variant is found in 1/218380 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. To our knowledge, neither multifactorial analysis nor well-stablished functional studies have been reported for this variant. It has been reported in ClinVar (2x LB, 5x VUS). Based on the currently available information, c.3263C>T is classified as a likely benign variant according to ClinGen-BRCA2 Guidelines version 1. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Uncertain:1

Feb 11, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3491C>T -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Mar 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 233378). 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. 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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1088 of the BRCA2 protein (p.Pro1088Leu). -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

6.2

DANN

Benign

0.24

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.073

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Benign

0.16

Sift

Benign

0.39

T;T

Sift4G

Benign

0.74

T;T

Vest4

0.30

MutPred

0.43

Loss of disorder (P = 0.0374);Loss of disorder (P = 0.0374);

MVP

0.84

MPC

0.034

ClinPred

0.36

GERP RS

4.4

gMVP

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over