13-32332343-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.865A>G(p.Asn289Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,445,970 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N289H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:9

Conservation

PhyloP100: 0.498

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15691748).

BP6

Variant 13-32332343-A-G is Benign according to our data. Variant chr13-32332343-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38176.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.865A>G	p.Asn289Asp	missense_variant	Exon 10 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.865A>G	p.Asn289Asp	missense_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.496A>G	p.Asn166Asp	missense_variant	Exon 10 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.865A>G		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

239502

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129342

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:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1445970

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

719086

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000611

Hom.:

122

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Sep 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24853695, 26483394, 25896959, 24504028, 29258903, 28814288, 27165220, 28324225) -

Sep 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PM2, BP1, BP4 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.865A>G (p.Asn289Asp) variant has been reported in the published literature to co-occur with the BRCA2 c.5864C>A (p.Ser1955*) pathogenic variant in multiple individuals (PMID: 25186627 (2015), BIC database (https://research.nhgri.nih.gov/projects/bic)), suggesting the c.865A>G (p.Asn289Asp) variant is not the primary cause of disease. However, this variant by itself has also been reported in individuals with breast/ovarian cancer (PMIDs: 32438681 (2020), 32284662 (2019), 28324225 (2017), 27165220 (2016), 25896959 (2015), 24504028 (2014)), and pancreatic cancer (PMID: 26483394 (2015)). The frequency of this variant in the general population, 0.000027 (3/110406 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 20, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

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). -

Jun 03, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 10, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:2

Aug 13, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose this criterion: BP1 (strong benign): (SpliceAI <=0.1) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Dec 07, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.865A>G (p.Asn289Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 314878 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.865A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other types of cancer (Wappenschmidt_2006, Cunningham_2014, Yang _2015, DArgenio_2015, Hu_2015, Tung_2015, Meisel_2017, Santonocito_2020, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with one specific pathogenic variant (BRCA2 c.5864C>A, p.Ser1955X) have been reported in patients, providing supporting evidence for a benign role (kConFab data, BIC data, Internal data, Tung_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24504028, 25896959, 26483394, 28324225, 36243179, 32438681, 25186627, 26535628, 35534704). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5) and likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer

Benign:1

Feb 07, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

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

0.082

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.16

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.87

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.11

T;T

Vest4

0.27

MutPred

0.17

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.86

MPC

0.022

ClinPred

0.24

GERP RS

1.7

gMVP

0.060

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