rs759383358
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP5_StrongBS1BP7_StrongBP4
This summary comes from the ClinGen Evidence Repository: The c.7521A>G variant in BRCA2 is a synonymous variant (p.Pro2507=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003057 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing (PMID:24489791), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.01 (based on Cosegregation LR=0.01), within the thresholds for Strong benign evidence (LR ≥0.00285 & <0.05) (BP5_Strong met; PMID:24489791).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP4, BP7_Strong (RNA), BP5_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025129/MONDO:0012933/097
Frequency
Consequence
NM_000059.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7521A>G | p.Pro2507= | synonymous_variant | 15/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7521A>G | p.Pro2507= | synonymous_variant | 15/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251394Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135866
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74398
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2015 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 27, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2021 | - - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Pro2507Pro variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. This variant was not identified in the literature. It was identified only once in the UMD databases and not in other BRCA2 locus specific databases. 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 predicted Benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 16, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2016 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 19, 2022 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
BRCA2-related cancer predisposition Benign:1
Benign, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Jun 11, 2024 | The c.7521A>G variant in BRCA2 is a synonymous variant (p.Pro2507=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0003057 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 24489791), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.01 (based on Cosegregation LR=0.01), within the thresholds for Strong benign evidence (LR >=0.00285 & <0.05) (BP5_Strong met; PMID: 24489791). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP4, BP7_Strong (RNA), BP5_Strong). - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 22, 2020 | 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). - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at