chr13-32340693-A-G
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.6338A>G(p.Asn2113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,608,786 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2113D) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
1
15
Clinical Significance
Conservation
PhyloP100: -1.03
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 Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.018149316).
BP6
Variant 13-32340693-A-G is Benign according to our data. Variant chr13-32340693-A-G is described in ClinVar as [Benign]. Clinvar id is 38039.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340693-A-G is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.6338A>G | p.Asn2113Ser | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6338A>G | p.Asn2113Ser | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000118 AC: 29AN: 244836Hom.: 0 AF XY: 0.000166 AC XY: 22AN XY: 132490
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GnomAD4 exome AF: 0.0000563 AC: 82AN: 1456562Hom.: 0 Cov.: 46 AF XY: 0.0000607 AC XY: 44AN XY: 724400
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GnomAD4 genome 0.000105 AC: 16AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74370
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:14
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:3
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Oct 14, 2014 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 08, 2006 | - - |
| Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000000117 - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not provided Uncertain:1Benign:2
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2017 | Variant summary: The BRCA2 c.6338A>G (p.Asn2113Ser) variant involves the alteration of a non-conserved nucleotide, which 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/119730 (1/14662), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals that have also classified the variant as "benign/neutral." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. In addition, BRCAshare, a reputable database that incorporates LCA samples indicates the variant co-occurred with another pathogenic BRCA2 variant, c.5576_5579delTTA in 3 individuals, along with an internal LCA sample reports the variant to co-occur with a BRCA1 pathogenic variant, c.68_29delAG. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. - |
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 27, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 04, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2014 | This alteration is classified as 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2015 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 30, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 03, 2021 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Asn2113Ser variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs80358874) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and two other submitters; as likely benign by four submitters; as uncertain significance by three submitters), MutDB, LOVD 3.0 (5x), UMD-LSDB (6x as likely neutral), BIC Database (13x), and in ARUP Laboratories (not pathogenic or of no clinical significance) databases. The variant was not identified in COGR, Cosmic, or the Zhejiang University Database. The variant was identified in control databases in 30 of 271298 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6322 chromosomes (freq: 0.0005), Latino in 6 of 33104 chromosomes (freq: 0.0002), European in 5 of 124988 chromosomes (freq: 0.00004), Ashkenazi Jewish in 16 of 9828 chromosomes (freq: 0.002), while the variant was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Asn2113 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to 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) do not predict a difference in splicing. In addition, a systematic genetic assessment and multifactorial probability based model identified the variant has odds in favor of neutrality 1749 and posterior probability of being deleterious 1.17√ó10-11 (Easton 2007, Lindor 2012). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
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
Uncertain
D;D
Sift4G
Benign
T;T
Vest4
MVP
MPC
0.019
ClinPred
T
GERP RS
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