ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.927A>G (p.Ser309=) (rs80359806)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163993 SCV000214594 likely benign Hereditary cancer-predisposing syndrome 2015-01-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112864 SCV000145789 uncertain significance Breast-ovarian cancer, familial 2 2003-10-29 no assertion criteria provided clinical testing
Color RCV000163993 SCV000689188 likely benign Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112864 SCV000744397 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502814 SCV000591719 likely benign not specified 2016-07-28 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112864 SCV000579056 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; http://priors.hci.utah.edu/PRIORS/).
GeneDx RCV000502814 SCV000730714 benign not specified 2015-05-05 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000112864 SCV000743253 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587846 SCV000695232 likely benign not provided 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.927A>G (p.Ser309Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 in silico tools via Alamut predict no significant effect on splicing for this variant. The variant does not lie within a known functional domain (InterPro) and one in silico tool (Mutation Taster) predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000415 (5/120434 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been cited in several publications. One publication, Garre_CG_2014, performed a family study which showed that the proband, the proband's affected father, and the proband's affected paternal uncle all carried the variant and had been diagnosed with colorectal cancer. However, the proband's mother, who also had been diagnosed with colorectal cancer, did not carry the variant. Additionally, the variant of interest is linked in cis with another variant, c.7759C>T (p.Leu2587Phe), which the authors proposed as a potential cancer risk allele. This data is supported by the findings in the UMD database where 14 of 14 records show the c.7759C>T variant co-occuring with the variant of interest. Furthermore the variant was found in two sisters in BIC, one of whom is unaffected, suggesting a benign outcome for this variant. While the age of the sisters was not given in the BIC database, a publication from the depositor (Xia_BRCA1&2_Thesis_2002) states "the mean baseline age for unaffected individuals was 65.1 (95% CI: 62.2-67.9)", making it very likely that the unaffected sister is beyond the average age of onset and provides a second case where the variant did not co-segregate with disease within a family. Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Invitae RCV000045778 SCV000073791 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-24 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000163993 SCV000805249 likely benign Hereditary cancer-predisposing syndrome 2018-04-06 no assertion criteria provided clinical testing

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