13-32398602-A-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):c.10089A>G(p.Ile3363Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign 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. I3363V) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
16
Clinical Significance
Conservation
PhyloP100: -1.51
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.033557475).
BP6
Variant 13-32398602-A-G is Benign according to our data. Variant chr13-32398602-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51039.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4, Benign=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.10089A>G | p.Ile3363Met | missense_variant | 27/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.10089A>G | p.Ile3363Met | missense_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251202Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135774
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GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461630Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45AN XY: 727128
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GnomAD4 genome 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 28, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 10, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Molecular Diagnostics, Rajiv Gandhi Cancer Institute & Research Center | Dec 28, 2016 | - - |
not specified Uncertain:2Benign:1
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 26, 2024 | Variant summary: BRCA2 c.10089A>G (p.Ile3363Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251202 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.10089A>G has been reported in the literature as a VUS in individuals with breast cancer and in settings of multigene cancer panel testing (example, Cunningham_2014, Mehta_2018, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally it has been observed in 2/9884 subjects in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24504028, 31159747, 30555256). ClinVar contains an entry for this variant (Variation ID: 51039). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 03, 2021 | DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.10089A>G, in exon 27 that results in an amino acid change, p.Ile3363Met. This sequence change has been described in gnomAD with a frequency of 0.065% in the South Asian sub-population (dbSNP rs80358390). The p.Ile3363Met change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ile3363Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in two individuals with ovarian cancer (PMIDs: 30555256). Due to the lack of sufficient evidences and functional studies,, the clinical significance of the p.Ile3363Met change remains unknown at this time. - |
not provided Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 31, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2019 | This variant is associated with the following publications: (PMID: 28099906, 24504028, 30555256, 31159747, 10923033, 31131967) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 14, 2023 | BP4 - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ile3363Met variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs80358390) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity; classified likely benign by Invitae, GeneDx and uncertain significance by Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano, BIC and Centre for MolecularDiagnostics & Cell Biology (Rajiv Gandhi Caner Institute & Research Center)), Clinvitae (4x), UMD-LSDB (2x as 3-UV), BIC Database (1x with clinical importance unknown, classification pending), and in control databases in 24 of 276930 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24010 chromosomes (freq: 0.00004), European Non-Finnish in 2 of 126512 chromosomes (freq: 0.00002), and South Asian in 21 of 30772 chromosomes (freq: 0.0007). while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Ile3363 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood Met impacts the protein; however, this information is not predictive enough to rule out 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Vest4
MVP
MPC
0.020
ClinPred
T
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gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at