13-32326500-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_000059.4(BRCA2):c.518G>T(p.Gly173Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,451,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G173C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.00006827

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32326499-G-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2415537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.518G>T	p.Gly173Val	missense_variant, splice_region_variant	Exon 7 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.518G>T	p.Gly173Val	missense_variant, splice_region_variant	Exon 7 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.149G>T	p.Gly50Val	missense_variant, splice_region_variant	Exon 7 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.518G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251340

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135838

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000827

AC:

AN:

1451340

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722676

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000907

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Oct 06, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.518G>T, located in exon 7 of the BRCA2 gene, is predicted to result in the substitution of Glycine by Valine at codon 173,p.(Gly173Val). This position is outside a (potentially) clinically important functional domain. The SpliceAI algorithm predicts no significant impact on splicing; however, minigene splicing studies have reported conflicting results. One study observed an increase in exon 7 skipping (PMID: 20215541), while another, using a different experimental design, found an exon 7 skipping proportion comparable to that of the wild-type control (PMID: 23983145). Additionally, a complementation assay using cDNA plasmid transfection demonstrated that this missense change has a neutral impact on homologous recombination repair (PMID: 21671020). c.518G>T is found in 3/268204 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. This variant has been reported in the ClinVar database (1x likely benign, 4x uncertain significance) and in the LOVD database (3x NA, 1x uncertain significance) but it remains "not yet reviewed" in the BRCA Exchange database. Based on currently available information, the variant c.518G>T should be considered an uncertain significance variant according to ClinGen-BRCAs Guidelines version 1.0.0. -

Jul 28, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with valine at codon 173 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). Functional RNA studies using minigene splicing assays reported conflicted findings of a partial splicing defect and no detectable defect (PMID: 20215541, 23983145). This variant has been reported in an individual with suspected hereditary breast cancer (PMID: 28205045) and another individual affected with triple-negative breast cancer (PMID: 25682074). This variant has been identified in 3/251340 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. -

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G173V variant (also known as c.518G>T), located in coding exon 6 of the BRCA2 gene, results from a G to T substitution at nucleotide position 518. The glycine at codon 173 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified in a cohort of high-risk breast and ovarian cancer patients (Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150). A functional assay shows that this alteration behaved like wildtype in a spontaneous homologous repair assay, however, the assay was not robust enough to predict clinical relevance of tested variants (Balia C et al. Breast Cancer Res. Treat., 2011 Oct;129:1001-9). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, the literature harbors conflicting results in terms of the generation of abnormal transcripts from a splicing minigene assay with one paper reporting exon 7 skipping as a minor isoform while another reports no abnormal transcripts (Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Di Giacomo D et al. Hum. Mutat., 2013 Nov;34:1547-57). This amino acid position is conserved on limited sequence alignment. 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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the BRCA2 protein (p.Gly173Val). This variant is present in population databases (rs28897702, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25682074, 28205045). ClinVar contains an entry for this variant (Variation ID: 51810). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 21671020). 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. -

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

0.18

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.57

M_CAP

Benign

0.079

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.78

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.31

T;T

Vest4

0.43

MutPred

0.23

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.86

MPC

0.17

ClinPred

0.37

GERP RS

0.56

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000068

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.010

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