ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2351C>T (p.Ser784Leu) (rs55914168)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
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) RCV000031045 SCV001161494 benign Breast-ovarian cancer, familial 1 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 = 0.000071
Invitae RCV001082662 SCV000075822 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131345 SCV000186320 likely benign Hereditary cancer-predisposing syndrome 2019-04-15 criteria provided, single submitter clinical testing Other data supporting benign classification
GeneDx RCV000587427 SCV000210129 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2351C>T at the cDNA level, p.Ser784Leu (S784L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, also denoted 2470C>T using alternate nomenclature, was observed in an individual with a personal and/or family history of breast and/or ovarian cancer (van der Hout 2006) as well as in 2/140 Latina women with breast cancer and a family history of breast and/or ovarian cancer, but was absent in 48 cancer-free Latina controls (McKean-Cowdin 2005). This variant was suggested to be benign based on functional analyses by Loke et al. (2015) which interrogated binding to multiple BRCA1 binding partners and DNA damage response. BRCA1 Ser784Leu was observed at an allele frequency of 0.12% (40/33556) in individuals of Latino ancestry in large population cohorts (Lek 2016). BRCA1 Ser784Leu is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser784Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000031045 SCV000487970 uncertain significance Breast-ovarian cancer, familial 1 2015-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255218 SCV000698944 benign not specified 2020-08-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2351C>T (p.Ser784Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. These in silico predictions have not been verified with functional studies, with one study classifying the variant as benign, based on a homozygous occurrence in a patient derived LCL sample, and therefore using it as a control in the study (Loke_2015). The variant allele was found at a frequency of 0.00018 in 250640 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.2351C>T, has been reported in the literature in individuals affected with tumors that belong to the HBOC spectrum, but without strong evidence for causality (e.g. Judkins_2005, McKean-Cowdin_2005, van der Hout_2006, Li_2018, Shao_2019, Abe_2019), moreover, in some of these studies, it was also found in healthy controls (McKean-Cowdin_2005, Li_2018). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.942_956delinsCTTACTTC (p.Arg1315fsX24) and RB1 c.1411C>T (p.Gln471X), in two internal LCA samples), providing supporting evidence for a benign role. In addition, a recent multifactorial likelihood analysis predicted this variant to be Benign (Parsons_2019). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x), likely benign (3x), or benign (2x; including the expert panel). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031045 SCV000743416 uncertain significance Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031045 SCV000744660 uncertain significance Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131345 SCV000902866 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587427 SCV001133525 benign not provided 2019-05-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587427 SCV001501179 likely benign not provided 2020-12-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031045 SCV000053639 likely benign Breast-ovarian cancer, familial 1 2009-08-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031045 SCV000144388 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356396 SCV001551554 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser784Leu variant was identified in 3 of 4154 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary breast and ovarian cancer and was present in 18 of 11,404 control chromosomes (frequency: 0.001) from healthy individuals (McKean-Cowdin 2005,van der Hout 2006, Li 2018, Fernandez-Lopez 2019). The variant was identified in dbSNP (rs55914168) as “with likely pathogenic, other allele”, ClinVar (classified as likely benign by Ambry Genetics, Invitae, Color and 2 other submitters and uncertain significance by GeneDx, Counsyl and 3 other submitters), LOVD 3.0 (observed 15x), UMD-LSDB (observed 2x). The variant was identified in control databases in 45 of 282,304 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 43 of 33,396 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24,966 chromosomes (freq: 0.00004), European in 1 of 128,600 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser784 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.