rs371278843
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_000059.4(BRCA2):c.8421G>A(p.Ser2807Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,446 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 4 hom. )
Consequence
BRCA2
NM_000059.4 synonymous
NM_000059.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.249
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 -15 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 13-32370491-G-A is Benign according to our data. Variant chr13-32370491-G-A is described in ClinVar as [Benign]. Clinvar id is 182299.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370491-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.249 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8421G>A | p.Ser2807Ser | synonymous_variant | 19/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8052G>A | p.Ser2684Ser | synonymous_variant | 19/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*479G>A | non_coding_transcript_exon_variant | 18/26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*479G>A | 3_prime_UTR_variant | 18/25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.0000592 AC: 9AN: 152048Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000342 AC: 86AN: 251344Hom.: 1 AF XY: 0.000464 AC XY: 63AN XY: 135850
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GnomAD4 exome AF: 0.000186 AC: 272AN: 1461398Hom.: 4 Cov.: 31 AF XY: 0.000263 AC XY: 191AN XY: 727058
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GnomAD4 genome 0.0000592 AC: 9AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74264
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ClinVar
Significance: Benign
Submissions summary: Benign:15
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:3
| Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 29, 2017 | Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0028 (South Asian), derived from ExAC (2014-12-17). - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2019 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 2014 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 16, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 31, 2021 | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2014 | 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 31, 2018 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
| Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 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 | May 01, 2023 | - - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser2807Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs371278843) “With Likely benign allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as a benign variant by GeneDx; classified as likely benign by Ambry Genetics), GeneInsight COGR database (1X, classified as “likely benign” by a clinical laboratory), and UMD (1X as a UV variant). This variant was identified in the Exome Variant Server project in 1 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). The variant was also identified in 46 of 16508 individuals from South Asia (frequency: 0.0028) and once in homozygous state, increasing the likelihood this variant does not have clinical significance. It was also identified in one East Asian and one African individual, increasing the likelihood this could be a low frequency benign variant in certain populations of origin. The p.Ser2807Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. It should be noted that another variant at the same position (c.8421G>T, p.Ser2807Ser) did not show splicing aberration and classified as Class 2, likely not pathogenic, according to the IARC 5 class system (Thomassen 2012). In summary, based on the above information this variant is classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at