rs80359076
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
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8351G>A | p.Arg2784Gln | missense_variant | 19/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8351G>A | p.Arg2784Gln | missense_variant | 19/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151862Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251422Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727084
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151862Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74162
ClinVar
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 | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PS3, PS4_STR - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 21, 2012 | - - |
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) - |
not provided Pathogenic:2Uncertain:2
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 | - - |
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 | GeneDx | May 08, 2023 | Multifactorial 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 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 | - - |
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 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | 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. - |
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). - |
Familial cancer of breast Uncertain:2
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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
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, criteria provided, single submitter | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at