ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7521A>G (p.Pro2507=)

gnomAD frequency: 0.00001  dbSNP: rs759383358
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000191161 SCV004101438 benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-10-12 reviewed by expert panel curation 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).
Ambry Genetics RCV000163178 SCV000213699 benign Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Invitae RCV001084279 SCV000253037 likely benign Hereditary breast ovarian cancer syndrome 2024-02-01 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University RCV000240774 SCV000265957 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
GeneDx RCV000444567 SCV000512387 benign not specified 2015-03-18 criteria provided, single submitter clinical testing 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.
Color Diagnostics, LLC DBA Color Health RCV000163178 SCV000683882 benign Hereditary cancer-predisposing syndrome 2022-01-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759659 SCV000889130 benign not provided 2021-04-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000444567 SCV000918949 likely benign not specified 2021-01-08 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000444567 SCV002068909 likely benign not specified 2018-03-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000759659 SCV000592119 likely benign not provided no assertion criteria provided clinical testing 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.

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