13-32380043-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.9154C>T(p.Arg3052Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,782 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3052Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9154C>T | p.Arg3052Trp | missense_variant | Exon 24 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8785C>T | p.Arg2929Trp | missense_variant | Exon 24 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1212C>T | non_coding_transcript_exon_variant | Exon 23 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*1212C>T | 3_prime_UTR_variant | Exon 23 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251190Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135794
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727192
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12Uncertain:1
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
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BRCA2 (p.Arg3052Trp): This sequence change results in a non-conservative amino acid change located in the OB3 domain of the encoded protein sequence. In-silico prediction show pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT vs 2 benign predictions from EIGEN and PrimateAI. It has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (PMID: 20513136 and 23108138). Functional analyses of this variant are published (PMID: 18451181, 23108138, 25146914, 18607349) describing it as deleterious. ClinVar has an entry for this variant (ClinVar 52763) with 25 submissions, all described it as pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Therefore, this variant was classified as pathogenic. -
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PS3; PP3; PP1; Expert panel -
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not provided Pathogenic:8
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Published functional studies demonstrate a damaging effect: impaired homology directed repair activity and cell survival, and increased sensitivity to PARP inhibitors (Farrugia et al., 2008; Kuznetsov et al., 2008; Guidugli et al., 2013; Cunningham et al., 2014; Hendriks et al., 2014; Shimelis et al., 2017; Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020); Observed in individuals with breast or ovarian cancer and reported to segregate with disease in affected family members (Mohammadi et al., 2009; Borg et al., 2010; Capanu et al., 2011; Cunningham et al., 2014; Song et al., 2014; Li et al., 2018); Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9382C>T; This variant is associated with the following publications: (PMID: 18607349, 19043619, 29555025, 28277317, 29176636, 21520273, 25556971, 26221963, 31565484, 30720243, 30078507, 31360874, 20513136, 25782689, 24504028, 24323938, 24728189, 23231788, 21702907, 19200354, 26026974, 20104584, 21120943, 24963051, 19563646, 23108138, 25146914, 18451181, 28199314, 28279176, 28283652, 28487467, 28724667, 25085752, 29339979, 29988080, 29922827, 30728895, 29907814, 26845104, 29446198, 30702160, 29607586, 31159747, 32444794, 34597585, 31980526, 30787465, 35273153, 31907386, 32438681, 29884136, 35264596, 35736817, 33609447, 32853339, 29884841, 31825140, 34399810, 33629534, 35711920, 12228710, 35665744, 21990134, 29394989) -
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The frequency of this variant in the general population, 0.000029 (1/34578 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer, ovarian cancer and in healthy controls (PMID: 28724667 (2017), 28283652 (2017), 26845104 (2016), 26221963 (2015), 24728189 (2014), 24504028 (2014), 21520273 (2011), 19563646 (2009), 19200354 (2009)). In addition, functional studies in the published literature demonstrate that this variant is damaging to BRCA2 protein function (PMID: 29394989 (2018), 28283652 (2017), 25146914 (2014), 18607349 (2008), 18451181 (2008)) and has been classified as pathogenic in multifactorial analyses (PMID: 23108138 (2013), 20513136 (2010)). Based on the available information, this variant is classified as pathogenic. -
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The BRCA2 c.9154C>T; p.Arg3052Trp variant (rs45580035) is reported in the medical literature in individuals and families with breast cancer (Farrugia 2008, Lindor 2012, Pruss 2014, Shimelis 2017). The variant is also reported in ClinVar (Variation ID: 52763), but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 3052 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.821). Additionally, functional studies demonstrate reduced protein function (Farrugia 2008, Kuznetsov 2008) and odds ratio calculations conclude this variant is pathogenic (Farrugia 2008, Lindor 2012, Pruss 2014, Shimelis 2017). Considering available information, this variant is classified as pathogenic. References: Farrugia DJ et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. Kuznetsov SG et al. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008 Aug;14(8):875-81. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21. Pruss D et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat. 2014 Aug;147(1):119-32. Shimelis H et al. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Res. 2017 Jun 1;77(11):2789-2799. -
PP1_strong, PP3, PP4_moderate, PS3 -
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Hereditary breast ovarian cancer syndrome Pathogenic:6
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Variant summary: BRCA2 c.9154C>T (p.Arg3052Trp) results in a non-conservative amino acid change located in the OB3 domain of the encoded protein sequence. Five 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 251190 control chromosomes. c.9154C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Farrugia_2008, GomezGarcia_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Farrugia_2008, Kuznetsov_2008, Walker_2010). Ninteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3052 of the BRCA2 protein (p.Arg3052Trp). This variant is present in population databases (rs45580035, gnomAD 0.003%). This missense change has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 18451181, 19200354, 20104584, 24504028, 24728189, 25556971, 26845104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52763). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 18607349, 23108138, 25146914). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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This missense variant replaces arginine with tryptophan at codon 3052 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 the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920). This variant has been reported in over 12 individuals affected with breast or ovarian cancer and in 1 unaffected individual (PMID: 18451181, 24728189, 25682074, 26221963, 28724667, 33471991). This variant has been reported in several families affected with hereditary breast and ovarian cancer (PMID: 19200354, 25556971) and has been identified in 22 families among the CIMBA participants (PMID: 29446198). It has been shown that this variant segregates with disease with a likelihood ratio of 3.6 from 10 carrier families (PMID: 18451181). This variant has been identified in 3/251190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
The p.R3052W pathogenic mutation (also known as c.9154C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9154. The arginine at codon 3052 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous families and individuals with breast and/or ovarian cancer (Gómez García EB et al. Breast Cancer Res. 2009; 11(1):R8; Cunningham JM, Sci Rep 2014; 4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). This alteration has been classified as pathogenic or likely pathogenic by several studies utilizing the following line(s) of evidence: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and/or functional assay results (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16; Mohammadi L et al. BMC Cancer, 2009 Jun;9:211; Capanu M et al. Genet. Epidemiol., 2011 Jul;35:389-97; Lindor NM et al. Hum Mutat. 2012 Jan; 33(1):8-21). Additionally, several functional studies have found this alteration to be pathogenic (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81; Hendriks G et al. Hum. Mutat., 2014 Nov;35:1382-91; Guidugli L et al. Am. J. Hum. Genet., 2018 Jan; Mesman RLS et al. Genet Med 2019 02;21(2):293-302; Richardson ME at al. Am J Hum Genet 2021 03;108(3):458-468 ). Of note, this alteration is also designated as 9382C>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Familial cancer of breast Pathogenic:2
This is a single base substitution replacing Arginine with Tryptophan at codon 3052 of the BRCA2 protein. The arginine residue is highly conserved and there is a large physicochemical difference between arginine and tryptophan (Grantham Score 101). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. This variant has been described in the international literature in patients affected with breast cancer (PMID: 18451181, PMID: 19200354 , BMC Cancer. 2009, 9:211; PMID: 21520273, PMID: 24504028). Experimental studies have shown that this missense change results in the loss of DNA repair activity of the encoded protein product in vitro (PMID: 18451181,PMID: 18607349). The mutation database ClinVar contains entries for this variant (Variation ID: 52763). -
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Breast and/or ovarian cancer Pathogenic:1
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Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
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BRCA2-related cancer predisposition Pathogenic:1
This missense variant replaces arginine with tryptophan at codon 3052 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 the variant protein is defective in homology-directed DNA repair and fails to complement BRCA2-deficient mouse embryonic stem cells (PMID: 18451181, 18607349, 24323938, 29394989, 35711920). This variant has been reported in over 12 individuals affected with breast or ovarian cancer and in 1 unaffected individual (PMID: 18451181, 24728189, 25682074, 26221963, 28724667, 33471991). This variant has been reported in several families affected with hereditary breast and ovarian cancer (PMID: 19200354, 25556971) and has been identified in 22 families among the CIMBA participants (PMID: 29446198). It has been shown that this variant segregates with disease with a likelihood ratio of 3.6 from 10 carrier families (PMID: 18451181). This variant has been identified in 3/251190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Arg3052Trp variant was identified in 5 of 10664 proband chromosomes (frequency: 0.0005) from individuals or families with breast and ovarian cancer (Borg 2010, Cunningham 2014, Trujillano 2015, Song 2014). The variant was also identified in the following databases: dbSNP (ID: rs45580035) as "With Pathogenic allele", ClinVar (13x pathogenic, 1x uncertain significance), Clinvitae (6X pathogenic), LOVD 3.0 (reported 50x, predicted deleterious), UMD-LSDB (10 records, causal), BIC Database (8x, clinical importance unknown), and ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 246052 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 1 of 33572 chromosomes (freq: 0.00003), European in 1 of 111550 chromosomes (freq: 0.000009), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). The variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. Functional studies investigating the DNA break repair activity of p.Arg3052Trp showed reduced activity of this variant (Farrugia 2008, Guidugli 2013). A study using mouse embryonic stem cells and bacterial artificial chromosomes demonstrated that cells expressing p.Arg3052Trp did not survive, suggesting it to be deleterious (Borg 2010). The p.Arg3052 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at