13-32371041-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):c.8573A>G(p.Gln2858Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q2858H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 4.16

Publications

20 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 13-32371041-A-G is Benign according to our data. Variant chr13-32371041-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52625.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8573A>G	p.Gln2858Arg	missense_variant	Exon 20 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.8573A>G	p.Gln2858Arg	missense_variant	Exon 20 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8204A>G	p.Gln2735Arg	missense_variant	Exon 20 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*631A>G		non_coding_transcript_exon_variant	Exon 19 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*631A>G		3_prime_UTR_variant	Exon 19 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251234

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5208

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.642

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 18, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19043619, 21990134, 18375895, 21702907, 21990165, 16905680, 28678401, 28283652, 25348012, 10923033, 29641532, 29884841, 31131967) -

Aug 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:1

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2017

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified

Benign:2

Nov 23, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.8573A>G (p.Gln2858Arg) results in a conservative amino acid change located in the Tower domain (IPR015205) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251234 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8573A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Simard_2007, Spurdle_2008, Shimelis_2017). These data do not allow any conclusion about variant significance. Co-occurrences with pathogenic variants have been reported in the BIC database (BRCA1 c.1054G>T, p.Glu352X; BRCA1 c.2035A>T, p.Lys679X), providing supporting evidence for a benign role. In addition, a multifactorial probability based model utilized for performing systematic assessment of variants of unknown significance in the BRCA genes, which includes analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicts this variant to be likely not pathogenic or of little clinical significance (Lindor_2012). One publication, Hart_2018, reports the HDR activity of this variant to be similar to that of wild-type and classifies the variant as neutral. Seven ClinVar submitters (evaluation after 2014) cite this variant as likely benign (n=4) and as uncertain significance (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of evidence supporting an actionable outcome as outlined above, the variant was classified as benign. -

Apr 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Mar 25, 2019

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. -

Dec 28, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Uncertain:1

Apr 14, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2

Benign:1

Jun 24, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.086

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

-0.21

PhyloP100

4.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.022

D;D

Vest4

0.46

MVP

0.89

MPC

0.14

ClinPred

0.93

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.48

Mutation Taster

=80/20

polymorphism

(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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13-32371041-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over