ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8764A>G (p.Ser2922Gly) (rs80359132)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031769 SCV001161625 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000712
Invitae RCV000195383 SCV000073636 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000590809 SCV000210482 likely benign not provided 2019-12-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26023681, 19043619, 31131967, 31294896)
Ambry Genetics RCV000165036 SCV000215734 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing The p.S2922G variant (also known as c.8764A>G), located in coding exon 21 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8764. The serine at codon 2922 is replaced by glycine, an amino acid with similar properties. This alteration was seen in a patient diagnosed with breast cancer at 33 (Foley SB et al. EBioMedicine. 2015 Jan;2(1):74-81). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000165036 SCV000683997 likely benign Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590809 SCV000695182 likely benign not provided 2016-04-15 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/119794, which does not exceed the predicted maximal expected allele frequency of a pathogenic BRCA2 variant of 1/1333. The variant of interest has been reported in an affected individual via publication(s), although with limited information (ie lack of co-occurrence, co-segregation data). Our laboratory received a Myriad report for a patient, in which Myriad reports the variant of interest to co-occur with a pathogenic BRCA2 variant, c.4480_4483delAGTG (legacy name: 4708del4, p.Val1495fsX8 - scored as pathogenic by Myriad)(Internal LCA data), indicating the missense variant of interest to be in the benign spectrum. Additionally, BIC cites the variant to co-occur with a pathogenic BRCA2 variant, c.4478_4481delAAAG (p.Glu1493fs - classified as pathogenic by LCA). Multiple reputable databases/clinical laboratories cite the variant with conflicting classifications "uncertain signifcance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590809 SCV001133948 uncertain significance not provided 2019-04-25 criteria provided, single submitter clinical testing
Mendelics RCV000031769 SCV001139233 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642491 SCV001852812 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031769 SCV000054377 likely benign Breast-ovarian cancer, familial 2 2009-03-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031769 SCV000147457 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045623 SCV000592229 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser2922Gly variant was identified in 1 of 516 proband chromosomes (frequency: 0.00193) from an individual with breast cancer (Foley_2015). The variant was also identified in a cohort of high-risk breast/ovarian cancer families, with the pathogenicity assessed to be inconclusive using the protein likelihood ratio model, a bioinformatics tool to predict whether a missense variant affects protein function (Karchin_2008). The variant was also identified in dbSNP (ID: rs80359132) as “With other allele”, ClinVar (with conflicting interpretations of pathogenicity (as likely benign by SCRP and as uncertain significance by Invitae, GeneDx, Ambry Geneticvs, COGR, and BIC)), Clinvitae (with conflicting interpretations of pathogenicity), COGR (as uncertain significance), Cosmic (as pathogenic, found in ovarian cancer ), LOVD 3.0 (2x as "inconclusive"), and the BIC Database (1x as "unknown clinical importance"). The variant was not identified in MutDB, UMD-LSDB, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 276204 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23950 chromosomes (freq: 0.000042), and European (Non-Finnish) in 1 of 125972 chromosomes (freq: 0.000008); but not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Ser2922Gly residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.