rs80358871
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.631G>A(p.Val211Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000702 in 1,424,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense, splice_region
NM_000059.4 missense, splice_region
Scores
1
6
9
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.91
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-32326613-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 13-32326613-G-A is Pathogenic according to our data. Variant chr13-32326613-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32326613-G-A is described in Lovd as [Pathogenic]. Variant chr13-32326613-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.631G>A | p.Val211Ile | missense_variant, splice_region_variant | 7/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.631G>A | p.Val211Ile | missense_variant, splice_region_variant | 7/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.02e-7 AC: 1AN: 1424234Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 710436
GnomAD4 exome
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29
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GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 05, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Val211Ile variant has been previously reported in the literature in 8 of 64 proband chromosomes of individuals with hereditary breast and/or ovarian cancer. However, no control chromosomes were evaluated to establish the prevalence of the variant in the general population (Colombo 2009, Pensabene 2009, Lowery 2011, Gaildrat 2012, Diez 2009). The variant occurs in the last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Indeed, functional studies have shown that the variant altered the natural splice sites leading to exon skipping due to modification of the sequence of the 5' splice site (Pensabene 2009, Gaildrat 2012). The variant has also been reported twice in the UMD database as a variant of unknown significance, and 8 times in the BIC database as a clinically significant variant. In both the cases reported in the UMD database, the variant was found to co-occur with the pathogenic BRCA2 variant (c.7008-2A>T). This other variant is also being reported as co-occurring in this individual. In summary, based on the above information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 17, 2023 | Variant summary: BRCA2 c.631G>A (p.Val211Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, this variant disrupts the last nucleotide of exon 7, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site and one predicts the variant weakens the same 5' donor site. Several publications report experimental evidence that this variant disrupts mRNA splicing, leading to skipping or shortening of exon 7 (e.g., Pensabene_2009, Colombo_2009, Gaildrat_2012). The variant was absent in 250814 control chromosomes (gnomAD). c.631G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Azzollini_2016, Bayraktar_2012, Colombo_2009, Diez_2009, Evans_2003, Gaildrat_2012, Pensabene_2009, Minucci_2016). The variant was reported to co-occur in cis with variant c.7008-2A>T in many (e.g., Azzollini_2016, Colombo_2009, Gaildrat_2012, Pensabene_2009) but not all (e.g., Minucci_2016) of the reported individuals. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22009639, 23451180, 12960223, 22962691, 19542536, 19179552, 19423647, 27062684, 27125725). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 211 of the BRCA2 protein (p.Val211Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related cancers. In some cases, this variant occurred on the same chromosome as the c.7008-2A>T variant (PMID: 19179552, 19423647, 21934105, 27125725, 30613976, 31336956, 32438681, 32853339, 33804961). This variant is also known as 859G>A. ClinVar contains an entry for this variant (Variation ID: 52058). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19179552, 22962691, 23451180; Invitae). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2023 | Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Pensabene at al., 2009; Colombo et al., 2009; Colombo at al., 2013; Gaildrat et al., 2012; Fraile-Bethencourt et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 859G>A; This variant is associated with the following publications: (PMID: 12960223, 21934105, 19542536, 32438681, 32854451, 19179552, 19423647, 22962691, 27125725, 23983145, 20455026, 31512090, 30883759, 32444794, 31336956, 32380732, 32338768, 33810291, 29446198, 30613976, 33287145, 23451180, 35205366, 35411189, 35264596, 32853339) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 22, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in patients with hereditary breast and ovarian cancer, prostate cancer, male breast cancer, and pancreatic cancer (PMIDs: 33471991 (2021), 32853339 (2021), 32854451 (2020), 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 30613976 (2019), 31512090 (2019), 31336956 (2019), 27125725 (2016), 22009639 (2012), 21934105 (2011), 19423647 (2009), 19179552 (2009), 12960223 (2003)). In functional studies, this variant has been shown to disrupt splicing and lead to exon skipping and premature truncation of the protein (PMIDs: 30883759 (2019), 23451180 (2013), 22962691 (2012), 19423647 (2009)). Of note, this variant is frequently reported in cis with BRCA2 c.7008-2A>T (p.?), also reported in the literature as IVS13-2A>T (PMIDs: 32338768 (2020), 32058061 (2020), 32438681 (2020), 33287145 (2020), 31336956 (2019), 19423647 (2009), 19179552 (2009), 12960223 (2003)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA2 mRNA splicing. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 06, 2022 | ONLY INCLUDE IF PT HAS BOTH c.7008-2A>T and p.V211I (c.631G>A) BRCA2 VARIANTS The c.631G>A pathogenic mutation (also known as p.V211I and 859G>A), located in coding exon 6 of the BRCA2 gene, results from a G to A substitution at nucleotide position 631. The amino acid change results in valine to isoleucine at codon 211, an amino acid with highly similar properties; however, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. The c.7008-2A>T (also known as IVS13-2A>T) intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 13 in the BRCA2 gene. The c.631G>A and c.7008-2A>T alterations have been identified in cis in multiple individuals and families with HBOC (Gaildrat PJ et al. Med. Genet. 2012 Oct;49(10):609-17; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). These alterations have also been identified in cis in one individual with pancreatic adenocarcinoma (Lowery MA et al. Oncologist 2011;16(10):1397-402). Functional studies have demonstrated that the c.631G>A alteration leads to the skipping of coding exon 6, leading to a frameshift and alternate stop in coding exon 8 (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4). Functional studies have also demonstrated that the c.7008-2A>T alteration leads to multiple transcripts of different lengths, most of which lead to a frameshift and alternate stop codon (Ambry internal data; Pensabene M et al. Ann. Oncol. 2009 May;20(5):874-8; Colombo M et al. Ann. Oncol. 2009 Jun;20(6):1143-4; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Colombo M et al. PLoS ONE 2013;8(2):e57173). Based on the available evidence, the mutations c.631G>A and c.7008-2A>T are classified as a pathogenic haplotype. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 20, 2021 | This variant alters the last nucleotide of BRCA2 exon 7 from c.G to c.A. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using patient-derived cells (PMID 19179552, 19423647, 23451180) and a mini-gene splicing assay (PMID: 22962691) have demonstrated that this variant causes a complete skipping of exon 7 and premature truncation. This variant has been reported in an individual affected with bilateral breast and ovarian cancer with family history of ovarian cancer and pancreatic cancer in the paternal grandmother and father, respectively (PMID: 27125725). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. This variant also has been reported to co-occur with c.7008-2A>T in the BRCA2 gene in at least seven unrelated European individuals affected with breast/ovarian cancer (PMID: 19179552, 19423647, 23451180, 27125725, 31336956) and in an individual affected with pancreatic adenocarcinoma (PMID: 21934105). In six of the individuals affected with breast/ovarian cancer, these variants were reported to occur on the same chromosome (in cis phase) determined in part by retro-transcription analysis or segregation analysis in family studies (PMID: 19179552, 19423647, 22962691, 31336956). For several individuals who carried both variants (PMID: 21934105; Color internal data), the phase of the two variants has not been determined. These two variants have not been reported in trans in the literature. Therefore, although this test cannot distinguish if c.631G>A and c.7008-2A>T variants occur on the same chromosome (in cis) or on opposite chromosomes (in trans), it is likely that these variants are in cis when found together in an individual. Medical management should be considered based on the patient's personal and family history. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | - | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 08, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of glycosylation at S206 (P = 0.1112);Loss of glycosylation at S206 (P = 0.1112);
MVP
MPC
0.092
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at