13-32380116-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_SupportingPS3PP4_StrongPP3

This summary comes from the ClinGen Evidence Repository: The variant c.9227G>T in BRCA2 is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 3076 (p.Gly3076Val). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.398, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:33609447) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3104.98 (based on Cosegregation LR=770.85; Pathology LR=1.89; Co-occurrence LR=1.08; Family History LR=1.98), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID:31853058, Internal lab contributors).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 (PM2_Supporting, PP3, PS3, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA026041/MONDO:0012933/097

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6U:2

Conservation

PhyloP100: 9.00

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS3

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

PM2

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

PP3

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.9227G>T	p.Gly3076Val	missense_variant	Exon 24 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.9227G>T	p.Gly3076Val	missense_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.8858G>T	p.Gly2953Val	missense_variant	Exon 24 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.*1285G>T		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2 link	n.*1285G>T		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1Uncertain:2

Mar 07, 2011

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

PS3(Strong)+PM2(Supporting)+PP3(Supporting)+PP4(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jan 16, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G3076V pathogenic mutation (also known as c.9227G>T), located in coding exon 23 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9227. The glycine at codon 3076 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified in a cohort of 418 Southern Brazilian HBOC probands (Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630). Homology-directed DNA repair (HDR) assays have demonstrated this variant to be non-functional (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). Internal structural analysis indicates that this amino acid substitution will be strongly destabilizing to the local structure and may affect binding to APRIN and PALB2 (Yang H et al. Science. 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is completely conserved on sequence alignment. This alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Sep 21, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with valine at codon 3076 in the DNA binding domain of the BRCA2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of homology directed repair activity of the BRCA2 protein (PMID: 23108138, 33609447). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 32814805, 33007869). It has been shown that this variant segregates with disease in at least one HBOC family (PMID: 32814805). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Oct 09, 2018

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (25.3) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (4), BIC (2), and BRCA2 LOVD (1). -

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

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 3076 of the BRCA2 protein (p.Gly3076Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 29161300, 30254663, 32814805). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126203). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138, 29394989). This variant disrupts the p.Gly3076 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12569143, 22711857, 23108138, 29394989, 30078507). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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 variant c.9227G>T in BRCA2 is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 3076 (p.Gly3076Val). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.398, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3104.98 (based on Cosegregation LR=770.85; Pathology LR=1.89; Co-occurrence LR=1.08; Family History LR=1.98), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31853058, Internal lab contributors). 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 (PM2_Supporting, PP3, PS3, PP4_Very strong). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

PhyloP100

9.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

N;N

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.83

MutPred

0.75

Gain of catalytic residue at G3076 (P = 0.0256);Gain of catalytic residue at G3076 (P = 0.0256);

MVP

0.98

MPC

0.18

ClinPred

0.98

GERP RS

5.5

gMVP

0.76

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over