ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2773A>C (p.Ile925Leu) (rs4986847)

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
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031070 SCV000244328 benign Breast-ovarian cancer, familial 1 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 = 0.00000326
Invitae RCV001085981 SCV000075980 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV001703432 SCV000209946 likely benign not provided 2021-03-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16518693, 22753008, 21990134, 18951461, 24853695, 24728327, 24729269, 17719744, 15235020, 17924331, 18951446, 23056176, 10923033, 22516946, 16267036, 25011685, 15385441)
Ambry Genetics RCV000162517 SCV000212911 benign Hereditary cancer-predisposing syndrome 2014-11-18 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 RCV000031070 SCV000488507 benign Breast-ovarian cancer, familial 1 2016-04-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000475644 SCV000540985 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162517 SCV000688400 likely benign Hereditary cancer-predisposing syndrome 2016-05-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120274 SCV000698978 benign not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2773A>C (p.Ile925Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251016 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.2773A>C has been reported in the literature in individuals affected with breast cancer and prostate cancer (example, Biunno_2014, Judkins_2005, Leongamornlert_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome (example, Easton_2007, Lindor_2012). At-least one co-occurrence with another pathogenic variant has been observed in our laboratory (BRCA1 c.1386delG, p.Thr464fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Research and Development, ARUP Laboratories RCV001659796 SCV001878269 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) RCV000031070 SCV000053666 likely benign Breast-ovarian cancer, familial 1 2006-06-20 no assertion criteria provided clinical testing
ITMI RCV000120274 SCV000084426 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000031070 SCV000144543 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353708 SCV000591411 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Ile925Leu variant was identified in 2 of 40118 proband chromosomes (frequency: 0.0002) from individuals or families with Breast and Ovarian Cancer in a Sudanese and other populations (Abkevich 2004, Biunno 2014).The variant was identified by our laboratory in 1 individual with ovarian cancer. The variant was also identified in dbSNP (ID: rs rs4986847, with a minor allele frequency of 0.0002 (1000 Genomes Project); NHLBI Exome Sequencing Project (Exome Variant Server) in 4 of 4406 African Americans and 0 of 8600 European Americans; Exome Aggregation Consortium (ExAC) database in 12 of 10402 Africans and 1 of 11564 Latino, and not found in European (Non-Finnish),East Asian, South Asian, European (Finnish) or other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, the ClinVar database (classified as a Likely Benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; as likely Benign by GeneDX; as uncertain significance by BIC; as Benign by Ambry Genitics; ITMI and Invitae did not provide a classification). In the BIC database it was identified 4X with unknown clinical importance, and UMD (2X as an unknown variant). The p.Ile925 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 p.Ile925Leu 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. 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 predicted benign.

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.