ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6921A>G (p.Ser2307=) (rs181183366)

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Total submissions: 13
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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) RCV000409129 SCV000579101 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 RCV000160238 SCV000210639 benign not specified 2014-09-19 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.
Ambry Genetics RCV000163368 SCV000213906 likely benign Hereditary cancer-predisposing syndrome 2014-10-14 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 RCV000196553 SCV000253032 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000196553 SCV000383750 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000377750 SCV000383751 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000409129 SCV000489320 likely benign Breast-ovarian cancer, familial 2 2016-09-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163368 SCV000683827 likely benign Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589859 SCV000695007 likely benign not provided 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6921A>G (p.Ser2307Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/116362 control chromosomes at a frequency of 0.0000172, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in a BrC patient without strong evidence for causality. In addition, five out of 6 clinical diagnostic laboratories/reputable databases classified this variant as likely benign and one lab classified it as benign, all without evidence for independent evaluation. Taken together, this variant is classified as Likely Benign.
PreventionGenetics,PreventionGenetics RCV000589859 SCV000805752 likely benign not provided 2017-08-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589859 SCV000883496 likely benign not provided 2018-01-16 criteria provided, single submitter clinical testing The BRCA2 c.6921A>G; p.Ser2307Ser variant (rs181183366) is reported in the medical literature in an individual with breast cancer (Borg 2010), but is also reported as benign or likely benign in the ClinVar database (Variation ID: 182293). The variant is listed in the Genome Aggregation Database in 15 out of 276360 alleles. This is a silent variant, the nucleotide at this position is weakly conserved across species, and computational algorithms predict this variant does not alter mRNA splicing. Considering available information, this variant is classified as likely benign. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589859 SCV000889114 likely benign not provided 2019-06-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354273 SCV001548847 likely benign Endometrial carcinoma no assertion criteria provided clinical testing The BRCA2 p.Ser2307 was identified in 1 of 4206 proband chromosomes (freq: 0.0002) from individuals with breast cancer (Borg 2010). The variant was identified in dbSNP (rs181183366) as “with other allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color, Counsyl and 7 other submitters; and as benign by GeneDx), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 15 of 281,468 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 15 of 24,546 chromosomes (freq: 0.0006); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Ser2307= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, 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 likely benign.

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