rs81002852
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):c.7435+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7435+6G>A | splice_region_variant, intron_variant | Intron 14 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.7066+6G>A | splice_region_variant, intron_variant | Intron 14 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.7435+6G>A | splice_region_variant, intron_variant | Intron 13 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.000526 AC: 80AN: 152186Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000216 AC: 54AN: 250250Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135436
GnomAD4 exome AF: 0.000103 AC: 150AN: 1461200Hom.: 1 Cov.: 34 AF XY: 0.000100 AC XY: 73AN XY: 726920
GnomAD4 genome AF: 0.000538 AC: 82AN: 152304Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 41AN XY: 74466
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:5
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 15, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 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, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 c.7435+6G>A variant was identified in 2 of 124 proband chromosomes (frequency: 0.016) from individuals or families with hereditary breast or ovarian cancer (Thomassen 2012, Whiley 2011); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs81002852) “With other allele” in the 1000 Genomes Project in 3 of 3000 chromosomes (frequency: 0.001), Exome Variant Server project in 12 of 4404 African American alleles, 0.0027), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also found in the ClinVar database with conflicting data from submitters, the BIC database (14 X with unknown clinical importance), and UMD (13 X as an unknown variant). In UMD the variant was identified with one co-occurring pathogenic BRCA1 variant c.2477_2478delCA (p.Thr826ArgfsX4) and one co-occuring BRCA2 pathogenic variant c.48dup (p.Thr17AspfsX14), increasing the likelihood that the c.7435+6G>A variant does not have clinical significance. The c.7435+6G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. In addition, in vitro analysis of mRNA in two studies indicated no splicing alterations (Thomassen 2012, Whiley 2011). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 24, 2016 | - - |
Uncertain significance, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Dec 23, 2014 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 23, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Vantari Genetics | Feb 05, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2015 | 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jun 27, 2023 | - - |
Likely benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2025 | - - |
Benign, no assertion criteria provided | research | Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology | Mar 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Sep 10, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 03, 2009 | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | Sep 02, 2022 | - - |
BRCA2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 22, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at