ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9606G>C (p.Pro3202=) (rs755890067)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000495413 SCV000578903 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Ambry Genetics RCV000163813 SCV000214397 likely benign Hereditary cancer-predisposing syndrome 2014-09-15 criteria provided, single submitter clinical testing This alteration is classified as likely 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 RCV000199254 SCV000253062 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000433154 SCV000512400 likely benign not specified 2017-10-27 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000433154 SCV000600871 likely benign not specified 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163813 SCV000684077 benign Hereditary cancer-predisposing syndrome 2016-05-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000433154 SCV000918912 likely benign not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9606G>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251382 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.9606G>C has been reported in the literature in affected individuals without strong evidence for causality (Borg_2010, Caux-Moncoutier_2011, Minucci_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4183C>T (p.Gln1395X); UMD database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (4x) / benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287475 SCV001474168 likely benign none provided 2020-03-18 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000163813 SCV000787961 likely benign Hereditary cancer-predisposing syndrome 2018-01-15 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355767 SCV001550739 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Pro3202= variant was identified in a cohort of ovarian cancer patients and classified as having no clinical significance (Minucci 2015). The variant was also identified in dbSNP (ID: rs755890067) as With Likely benign allele, ClinVar (classified as benign by Color Genomic and Invitae; classified as likely benign by Ambry Genetics, GeneDx, ENIGMA, and one other clinical laboratory), Clinvitae, LOVD 3.0 (4x), and UMD-LSDB (15x as uncertain significance; co-occurring with the pathogenic BRCA1 variant c.4183C>T, p.Gln1395X). The variant was not identified in GeneInsight-COGR, Cosmic, BIC Database, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 11 of 246166 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 11 of 111642 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro3202= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although available information suggests a benign role. This variant is classified as likely benign.

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