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rs80359076

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5

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. R2784L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

10
3
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000059.4
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr13-32370420-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.791
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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: {Uncertain_significance=10, Likely_pathogenic=5, 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 UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.8351G>A p.Arg2784Gln missense_variant 19/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.8351G>A p.Arg2784Gln missense_variant 19/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000132
AC:
2
AN:
151862
Hom.:
0
Cov.:
32
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:
3
AN:
251422
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
25
AN:
1461502
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000132
AC:
2
AN:
151862
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
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.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
?
    Exome Aggregation Consortium database
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain: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 providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)May 29, 2002- -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthOct 23, 2023This 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 submitterresearchCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 09, 2022PS3, PS4_STR -
Uncertain significance, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Aug 21, 2012- -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely benign, no assertion criteria providedclinical testingDepartment of Medical and Surgical Sciences, University of BolognaSep 01, 2023PS3(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) -
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 14, 2020- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalSep 11, 2014- -
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 08, 2023Multifactorial likelihood analysis suggests this variant is benign (Parsons et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in several families with BRCA2-related cancers, but also in healthy controls (Gmez Garca et al., 2009; Kote-Jarai et al., 2011; Stegel et al., 2011; Fernandes et al., 2016; Maistro et al., 2016; Zuntini et al., 2018; Dorling et al., 2021; Guindalini et al., 2022); 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 (Guidugli et al., 2013; Mesman et al., 2018; Guidugli et al., 2018; Hart et al., 2018; Iversen et al., 2022); 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, 31131967) -
Hereditary cancer-predisposing syndrome Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2023The 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 providedclinical testingTrue Health DiagnosticsFeb 20, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 18, 2023This 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 submittercurationSema4, Sema4Oct 21, 2021- -
Hereditary breast ovarian cancer syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 31, 2023This 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. -
Likely pathogenic, criteria provided, single submittercurationCancer Variant Interpretation Group UK, Institute of Cancer Research, LondonOct 04, 2020Data 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). -
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 09, 2024ACMG codes applied following ENIGMA VCEP rules: PS3, BP5_STR, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 19, 2023- -
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioFeb 17, 2023- -
Breast neoplasm Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 23, 2024The 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
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
32
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.79
D;D
MetaSVM
Uncertain
0.60
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.48
T
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
D
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.

Other links and lift over

dbSNP: rs80359076; hg19: chr13-32944558; API