ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8420C>T (p.Ser2807Leu) (rs55763607)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045513 SCV000073526 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130247 SCV000185091 benign Hereditary cancer-predisposing syndrome 2020-05-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
GeneDx RCV000588703 SCV000210471 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8420C>T at the cDNA level, p.Ser2807Leu (S2807L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). Using alternate nomenclature, this variant would be defined as BRCA2 8648C>T. This variant was predicted to be of uncertain clinical significance by a multifactorial likelihood model and homology-directed DNA break repair functional assay (Guidugli 2013). BRCA2 Ser2807Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2807Leu is located in the DSS1 contacting residue within the DNA binding domain (Yang 2002). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser2807Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000083147 SCV000487929 uncertain significance Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212274 SCV000600803 uncertain significance not specified 2016-09-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130247 SCV000689123 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588703 SCV000695152 uncertain significance not provided 2016-06-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8420C>T (p.Ser2807Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121394 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). One functional study has reported the variant to be classified as nonpathogenic via HDR assay (Guidugli_2012). However the variant has not been reported in affected individuals in the litature. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000130247 SCV000803160 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588703 SCV000887940 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000083147 SCV001429280 uncertain significance Breast-ovarian cancer, familial 2 2019-08-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083147 SCV000115221 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083147 SCV000147359 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353406 SCV000592189 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Ser2807Leu variant was identified in dbSNP (ID: rs55763607) “With uncertain significance allele”, the BIC database (1X with unknown clinical importance), and in the ClinVar database (classified with “uncertain significance” by four submitters: Ambry Genetics, GeneDX, Sharing Clinical Reports Project, BIC). The variant was listed in the Exome Aggregation Consortium (ExAC) database, where it was found in 3 of 11572 chromosomes from a cohort of Latino ethnicity; however this low frequency is not substantive enough to comment on the relationship of this variant to disease. The variant was not identified in other database searches, including: NHLBI Exome Sequencing Project (Exome Variant Server), ARUP Laboratories BRCA Mutations Database, COSMIC, LOVD, BRCA Share and the GeneInsight COGR database. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ser2807 residue is conserved across mammals and other organisms, and 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. One in silico study predicting the impact of the variant on protein function yielded inconclusive results (Karchin 2008), while a cell-based study assessing homology-directed repair concluded that the variant does not impact this function of the BRCA2 protein (Guidugli 2013). 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 unknown 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.