rs34355306
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000059.4(BRCA2):c.1275A>G(p.Glu425Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,608,514 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00047 ( 4 hom. )
Consequence
BRCA2
NM_000059.4 synonymous
NM_000059.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.10
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 13-32332753-A-G is Benign according to our data. Variant chr13-32332753-A-G is described in ClinVar as [Benign]. Clinvar id is 51093.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332753-A-G is described in Lovd as [Benign]. Variant chr13-32332753-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.1 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00319 (486/152330) while in subpopulation AFR AF= 0.0111 (461/41576). AF 95% confidence interval is 0.0103. There are 2 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1275A>G | p.Glu425Glu | synonymous_variant | 10/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.906A>G | p.Glu302Glu | synonymous_variant | 10/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.1275A>G | non_coding_transcript_exon_variant | 9/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00319 AC: 485AN: 152212Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00107 AC: 261AN: 243730Hom.: 2 AF XY: 0.000780 AC XY: 103AN XY: 132000
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GnomAD4 exome AF: 0.000471 AC: 686AN: 1456184Hom.: 4 Cov.: 35 AF XY: 0.000427 AC XY: 309AN XY: 724252
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GnomAD4 genome AF: 0.00319 AC: 486AN: 152330Hom.: 2 Cov.: 32 AF XY: 0.00318 AC XY: 237AN XY: 74488
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ClinVar
Significance: Benign
Submissions summary: Benign:26
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2013 | 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 20, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 11, 2014 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:5
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Jan 02, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), derived from 1000 genomes (2012-04-30). - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Sep 18, 2010 | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 31, 2023 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 09, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Likely benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 08, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 29, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2015 | 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. - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 09, 2023 | - - |
Fanconi anemia complementation group D1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
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.Glu425Glu variant was identified in 29 of 2532 proband chromosomes (frequency: 0.011) from individuals or families with breast cancer, and was not identified in 334 control chromosomes from healthy individuals (Fackenthal 2012, Han 2006, Kawahara 2004, Toh 2008). The variant was also identified in dbSNP (ID: rs34355306) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar and Invitae, as likely benign by ClinVar), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, GeneDx, Emory genetics, BIC, as likely benign by Counsyl and Ambry genetics), the BIC database (2x with no clinical importance), UMD (70x with a “unclassified variant” classification) and Fanconi Anemia Mutation Database (LOVD). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1: c.4986+6T>C, c.5468-2A>G and BRCA2: c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Glu425Glu variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 33 of 5000 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 43 of 4400 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 161 (2 homozygous) of 120508 chromosomes (freq. 0.001) in the following populations: African in 138 of 9866 chromosomes (freq. 0.01), East Asian in 20 of 8642 chromosomes (freq. 0.002), Latino in 3 of 11540 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant. The p.Glu425Glu 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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