13-32363225-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_StrongPVS1

This summary comes from the ClinGen Evidence Repository: The c.8023A>G variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 2675 (p.Ile2675Val). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and mini-gene assays demonstrated that the variant impacts splicing by creation of a donor site, resulting in skipping of 309nt of exon 18 (PMIDs: 18424508, 22505045, 28339459). All studies report no wild-type transcript from the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1612 (based on Cosegregation LR=605.1; Pathology LR=0.88; Co-occurrence LR=1.05; Family History LR=2.88), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID:31131967). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025410/MONDO:0012933/097

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 8.87

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 Pathogenic. Variant got 12 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8023A>G	p.Ile2675Val	missense_variant	Exon 18 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.8023A>G	p.Ile2675Val	missense_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7654A>G	p.Ile2552Val	missense_variant	Exon 18 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*81A>G		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*81A>G		3_prime_UTR_variant	Exon 17 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251076

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:5

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Feb 11, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in healthy controls and in individuals affected with breast or ovarian cancer in the published literature (PMID: 30652428 (2019), 30287823 (2018), 29907814 (2018), 29383094 (2017), 28993434 (2018)). Additionally, functional studies indicate that this variant interferes with normal BRCA2 mRNA splicing (PMID: 28339459 (2017), 22505045 (2012), 18424508 (2008)). 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 disease causing and damaging. Variant is located in potentially critical domain of the protein. Therefore, the variant is classified as pathogenic. -

Jul 12, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Exonic splice variant demonstrated to result in aberrant splicing, resulting in the in-frame deletion of 309 nucleotides (Bonnet 2014, Fraile-Bethencourt 2017); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (Lek 2016); Observed in multiple individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Blay 2013, Hirotsu 2015, Nakamura 2015, Fernandes 2016, Ng 2016, Sakamoto 2016); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Also known as 8251A>G; This variant is associated with the following publications: (PMID: 32377563, 31159747, 30720243, 30652428, 29176636, 31214711, 30287823, 28993434, 30415210, 29446198, 28111427, 12228710, 27535533, 29907814, 32862574, 33875706, 23683081, 25802882, 24249303, 27741520, 26757417, 26439132, 31131967, 28339459, 18424508, 22505045, 27157322) -

Feb 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Pathogenic:3

Jan 31, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and nonpolar, with valine, which is neutral and non-polar, at codon 2675 of the BRCA2 protein (p.Ile2675Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 103 amino acid residue(s), This nucleotide position is highly conserved. This variant is present in population databases (rs397507954, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Asp2723His) have been determined to be pathogenic (PMID: 15290653, 15695382, 16489001, 18607349, 23108138, 25146914). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 28, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Nov 19, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.8023A>G (p.Ile2675Val) results in a conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict that the variant creates a cryptic exonic 5-prime donor site. These predictions were confirmed by experimental evidence which demonstrated that the variant results in loss of a stretch of 309 nucleotides at the 3-prime terminal of exon 18 from the mRNA. Multiple studies observed abundant aberrant product and a complete absence of wild type product (Fraile-Bethencourt_2017, Houdayer_2012, Bonnet_2008). The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. c.8023A>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018, Hirotsu_2015, Blay_2013, Bonnet_2008, Palma_2008). These data indicate that the variant is very likely to be associated with disease. Six other ClinVar submitters (evaluation after 2014), including two expert panels, have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2675 of the BRCA2 protein (p.Ile2675Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 103 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs397507954, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). 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 with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 18 (PMID: 18424508, 22505045, 27157322, 28339459, 31191615; Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Asp2723His) have been determined to be pathogenic (PMID: 15290653, 15695382, 16489001, 18607349, 23108138, 25146914). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2020

GeneKor MSA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a missense mutation replaces Isoleucine with Valine at codon 2675 of the BRCA2 protein. The isoleucine residue is highly conserved in a functional domain of the protein and there is a small physiochemical difference between isoleucine and valine (Grantham Score 29). This sequence change is not present in population databases (rs397507954, no ExAC). It has been described in literature in individuals and families affected with breast and/or ovarian cancer (PMID: 18424508, PMID: 25802882, PMID: 26757417, PMID: 27741520, PMID: 27157322 ). ClinVar contains multiple entries for this variant (Variation ID: 52475). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be detrimental to protein function, a prediction which is supported by experimental RT-PCR and mini-gene splicing assays which show that this missense change creates a strong donor splice site, resulting in the removal of 309 nucleotides (r.8023_8331del) of exon 18 and the in-frame deletion of 103 amino acid residues (p.Ile2675_Lys2777del) (PMID: 22505045, PMID: 18424508 , PMID: 28339459 ). At least three different missense substitutions within the deleted region of BRCA2 (p.Thr2722Arg, p.Asp2723Gly, p.Asp2723His) are reported to be deleterious (PMID: 12145750 , PMID: 21990134 , PMID: 15290653, PMID: 16489001). This indicates that the residues included in the deleted region are important for BRCA2 protein function. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

May 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition

Pathogenic:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.8023A>G variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 2675 (p.Ile2675Val). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and mini-gene assays demonstrated that the variant impacts splicing by creation of a donor site, resulting in skipping of 309nt of exon 18 (PMIDs: 18424508, 22505045, 28339459). All studies report no wild-type transcript from the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1612 (based on Cosegregation LR=605.1; Pathology LR=0.88; Co-occurrence LR=1.05; Family History LR=2.88), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8023A>G variant (also known as p.I2675V), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8023. The isoleucine at codon 2675 is replaced by valine, an amino acid with highly similar properties. RNA studies have shown that this alteration creates a new donor site that results in an abnormal transcript with an in-frame loss of 309 nucleotides (Ambry internal data; Bonnet C et al. J Med Genet. 2008 Jul;45(7):438-46; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691). In addition, this alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Blay P et al. BMC Cancer. 2013 May;13:243; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Hirotsu Y et al. Mol Genet Genomic Med. 2015 Mar;3:121-9; Hirotsu Y et al. Oncotarget. 2017 Dec;8:114463-114473; Wen WX et al. J. Med. Genet. 2018 02;55:97-103; Liu Y et al. Mol Genet Genomic Med. 2019 03;7:e493; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.58

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.30

N;N

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.047

D;D

Vest4

0.84

MutPred

0.70

Gain of methylation at K2674 (P = 0.0639);Gain of methylation at K2674 (P = 0.0639);

MVP

0.92

MPC

0.16

ClinPred

0.95

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: -1

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