ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5710C>G (p.Leu1904Val)

gnomAD frequency: 0.00020  dbSNP: rs55875643
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
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) RCV000031571 SCV000244459 benign Breast-ovarian cancer, familial, susceptibility to, 2 2015-08-10 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 = 0.0000209
Invitae RCV001082023 SCV000072737 benign Hereditary breast ovarian cancer syndrome 2021-12-16 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148433 SCV000190132 likely benign Breast neoplasm 2014-06-01 criteria provided, single submitter research
GeneDx RCV000433189 SCV000210618 likely benign not provided 2021-01-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21990134, 24055113, 22848303, 15744044, 24323938, 25637381, 26689913, 17924331, 28814288, 32926152)
Ambry Genetics RCV000162807 SCV000213288 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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.
Counsyl RCV000031571 SCV000488170 benign Breast-ovarian cancer, familial, susceptibility to, 2 2016-01-13 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000433189 SCV000511375 likely benign not provided 2017-02-08 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Genetic Services Laboratory,University of Chicago RCV000044724 SCV000593747 likely benign not specified 2016-10-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000433189 SCV000694893 benign not provided 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5710C>G (p.Leu1904Val) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign 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 5/120788 (1/24160), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications and databases cite the variant in affected individuals, in which multiple individuals carried another pathogenic BRCA2 variant (c.3922G>T (p.Glu1308X), c.1813dup (p.Ile605AsnfsX11)) and BRCA1 (c.5324T>G (p.Met1775Arg - classified as pathogenic by LCA) and c.1949_1950delTA (p.Ile650LysfsX22)). In addition, multiple reputable clinical laboratories classify the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000433189 SCV000889076 benign not provided 2018-09-06 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162807 SCV000902851 benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Mendelics RCV000031571 SCV001139123 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000433189 SCV001477675 benign not provided 2020-01-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031571 SCV000054176 benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-12-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031571 SCV000146671 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000433189 SCV000591990 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Leu1904Val variant was identified in 3 of 638 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer and was not identified in 148 control chromosomes from healthy individuals (Fackenthal 2005, Zhou 2005, Diez 2011). The variant was also identified in dbSNP (ID: rs55875643) as "With Uncertain significance, other allele", ClinVar (classified as benign by ENIGMA, Counsyl, Invitae, Ambry Genetics, SCRP and one other clinical laboratory; as likely benign by GeneDx and four other clinical laboratories; and as uncertain significance by BIC), GeneInsight-COGR, MutDB, LOVD 3.0 (4x predicted neutral), UMD-LSDB (10x as likely neutral), BIC Database (8x with unknown significance), and ARUP Laboratories Database (not pathogenic or of no clinical significance). The variant was identified with the following co-occurring pathogenic variants: BRCA2 c.1813dup, p.Ile605Asnfs*11 (UMD database), BRCA1 c.1949_1950delTA, p.Ile650Lysfs*22 (Diez 2011), and BRCA2 c.7806-?_8632+?dup, p.Glu2878Glyfs*46 (our laboratory), increasing the likelihood that the p.Leu1904Val variant does not have clinical significance. The variant was not identified in Cosmic or the Zhejiang University database. The variant was identified in control databases in 14 of 276606 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 23996 chromosomes (freq: 0.0004), Other in 1 of 6450 chromosomes (freq: 0.0002), Latino in 1 of 34388 chromosomes (freq: 0.00003), and European in 2 of 126282 chromosomes (freq: 0.00002), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu1904 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The information in the literature is conflicting and limited to in silico models (Easton 2007, Lindor 2012, Guidugli 2014, Zhou 2005). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000044724 SCV002550352 benign not specified 2021-08-27 no assertion criteria provided clinical testing

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.