rs80359076

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3PP5

The NM_000059.4(BRCA2):c.8351G>A(p.Arg2784Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2784W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:14B:1

Conservation

PhyloP100: 9.94

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 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32370420-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

PP5

Variant 13-32370421-G-A is Pathogenic according to our data. Variant chr13-32370421-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52559.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=9, Pathogenic=1}. Variant chr13-32370421-G-A is described in Lovd as [Likely_pathogenic]. Variant chr13-32370421-G-A is described in Lovd as [Likely_pathogenic]. Variant chr13-32370421-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.8351G>A	p.Arg2784Gln	missense_variant	19/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.8351G>A	p.Arg2784Gln	missense_variant	19/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251422

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151862

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74162

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000249

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:14Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:2Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces arginine with glutamine at codon 2784 of the BRCA2 protein. Computational prediction 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 reduces homology-direct DNA repair function, complements poorly in BRCA2-null cells, and increases sensitivity to PARP inhibitors (PMID: 23108138, 29394989, 29988080, 37067535). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 34072659, 27914478, 36605468, DOI: 10.1515/tjb-2019-0424, Color internal data). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 6/60466 cases and 2/53461 controls, showing inconclusive association with disease (OR= 2.653, 95%CI 0.535 to 13.143, p-value= 0.296) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000310). A multifactorial analysis has reported low likelihood ratios based on segregation with disease in multiple families and co-occurrence with pathogenic variant(s) that might explain the disease (PMID: 31131967). This variant has been identified in 3/251422 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PS3(Strong)+PP3(Supporting)+BP5(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) -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 21, 2012	- -
Likely pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PS3, PS4_STR -

not provided

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2024	Observed in several families with BRCA2-related cancers, but also in healthy controls (PMID: 19200354, 21952622, 21232165, 27741520, 27914478, 30254663, 33471991, 35264596, 34326862, 35534704, 36881271); Published functional studies are conflicting: capable of rescuing cell lethality in a mouse-based complementation assay, but associated with damaging to partially damaging effects on homology-directed repair activity (PMID: 23108138, 29988080, 29394989, 29884841, 35665744); Multifactorial likelihood analysis suggests this variant is benign (PMID: 31131967); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8579G>A; This variant is associated with the following publications: (PMID: 19043619, 17088437, 27914478, 25032700, 29988080, 23108138, 21952622, 19200354, 19563646, 25637381, 27741520, 21232165, 29394989, 29884841, 30254663, 29641532, 35665744, 33471991, Bahsi2019[article], 32444794, 32719484, 35264596, 34072659, 36605468, 12228710, 30032850, 27616075, 37067535, 34326862, 35534704, 36881271, 38136308, 31131967) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 11, 2014	- -

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 18, 2023	This missense variant replaces arginine with glutamine at codon 2784 of the BRCA2 protein. Computational prediction 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 reduces homology-direct DNA repair function, complements poorly in BRCA2-null cells, and increases sensitivity to PARP inhibitors (PMID: 23108138, 29394989, 29988080, 37067535). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 34072659, 27914478, 36605468, DOI: 10.1515/tjb-2019-0424, Color internal data). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 6/60466 cases and 2/53461 controls, showing inconclusive association with disease (OR= 2.653, 95%CI 0.535 to 13.143, p-value= 0.296) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000310). A multifactorial analysis has reported low likelihood ratios based on segregation with disease in multiple families and co-occurrence with pathogenic variant(s) that might explain the disease (PMID: 31131967). This variant has been identified in 3/251422 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2023	The p.R2784Q variant (also known as c.8351G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8351. The arginine at codon 2784 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with breast cancer, ovarian cancer, and/or prostate cancer (Gómez García EB et al. Breast Cancer Res. 2009;11:R8; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Zuntini R et al. Front Genet, 2018 Sep;9:378; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Subaolu A et al. Eur J Breast Health, 2023 Jan;19:55-69). This variant was shown to be deleterious in several functional assays including assessment of homology-directed repair activity (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102;233-248, Hart SN. Genet Med . 2019 01;21(1):71-80) and sensitivity to cisplatin (Mesman RLS. Genet Med . 2019 02;21(2):293-302) and PARP inhibitors (Ikegami M et al. Nat Commun, 2020 05;11:2573). However one assay in embryonic stem cells showed this variant retained the ability to perform complementation, but showed reduced HDR activity (Mesman RLS et al. Genet Med . 2019 02;21(2):293-302). In addition, this variant has been classified as deleterious or likely deleterious by protein likelihood ratios and multiple in silico tools (Karchin R et al. Cancer Inform. 2008 May;6:203-16; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Hart SN et al. Genet. Med., 2019 01;21:71-80). However, a multifactorial likelihood analysis incorporating family history, tumor data and co-segregation information found this variant to be benign, acknowledging that this classification conflicts with functional data (Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). In addition, the alteration did not completely segregate with disease in several studies with multiple affected family members (Mohammadi L. BMC Cancer . 2009 Jun;9:211, Gómez García EB. Breast Cancer Res . 2009 Feb;11(1):R8). This amino acid position is highly conserved in available vertebrate species. The BayesDel in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 04, 2020	Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic BRCA1/BRCA2 testing for HBOC according to diagnostic criteria, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 1/55,830 gnomAD NFE controls) 2-sided Fishers exact: pexact= 0.13 (PS4_sup). This variant is predicted deleterious on AlignGVGD (class:C35), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (34) (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 (8), BIC (4), UMD (1) and BRCA2 LOVD (3). The frequency of this variant is 2/67,273 individuals (remainder of the gnomAD population). -
Likely pathogenic, low penetrance, no assertion criteria provided	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Oct 08, 2024	ENIGMA CWG (manuscript in preparation) Variant with reduced risk!!!; According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:29988080, 29884841, 32444794), PM3 (strong pathogenic): 2 times compound heterozygous in FA-patients ( IUGR, microcephaly Wilms-tumor age 8, , T-cell ALL (Phi+), age 3 ), PP3 (supporting pathogenic): BayesDel >0,3 inside clinically important domain, BP5 (very strong benign): Combined (Parsons LR/ACMG LLR) 8.73e-06 / -15.9 (new ENIGMA data in preparation) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2784 of the BRCA2 protein (p.Arg2784Gln). This variant is present in population databases (rs80359076, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer, prostate cancer, clinical features of Fanconi anemia and/or sarcoma (PMID: 19200354, 19563646, 21232165, 21952622, 27914478, 30254663, 34326862, 35264596; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52559). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19200354, 23108138, 29394989, 29988080, 31131967, 32444794). This variant disrupts the p.Arg2784 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16683254, 18451181, 21520333, 23108138, 27616075, 29884841, 29988080, 30032850). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2024	ACMG codes applied following ENIGMA VCEP rules: PS3, BP5_STR, PP3 -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 17, 2023

- -

Breast neoplasm

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

BRCA2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The BRCA2 c.8351G>A variant is predicted to result in the amino acid substitution p.Arg2784Gln. This variant has been reported in individuals and families affected with breast and/or ovarian cancer and prostate cancer (Gomez Garcia et al. 2009. PubMed ID: 19200354; Supplementary Table 1, Kote-Jarai et al. 2011. PubMed ID: 21952622; Maistro et al. 2016. PubMed ID: 27914478; Fernandes et al. 2016. PubMed ID: 27741520). It has also been reported in controls (Supplemental Content, Dorling et al. 2021. PubMed ID: 33471991). Experimental studies suggest this variant impacts protein function; however, these studies were conflicting regarding the extent of functional defect (Guidugli et al. 2018. PubMed ID: 29394989; Mesman et al. 2018. PubMed ID: 29988080). In a publication from the ENIGMA BRCA2 expert curation panel, they state that p.Arg2784Gln has conflicting functional and clinical data and is "considered uncertain according to ACMG/AMP qualitative criteria" (Parsons et al. 2019. PubMed ID: 31131967). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/52559/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

0.60

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.90

MVP

0.95

MPC

0.17

ClinPred

0.99

GERP RS

5.3

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

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