ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1534C>T (p.Leu512Phe) (rs41286294)

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) RCV000031001 SCV001161487 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 = 0.000143
Invitae RCV001084962 SCV000075530 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131272 SCV000186240 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);No disease association in small case-control study;Other data supporting benign classification
GeneDx RCV000047517 SCV000209929 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724518 SCV000224997 uncertain significance not provided 2015-01-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724518 SCV000296346 uncertain significance not provided 2019-11-04 criteria provided, single submitter clinical testing
Counsyl RCV000031001 SCV000488220 uncertain significance Breast-ovarian cancer, familial 1 2016-09-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047517 SCV000698872 likely benign not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1534C>T (p.Leu512Phe) 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. The variant allele was found at a frequency of 4e-05 in 276990 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.001), allowing no conclusion about variant significance. c.1534C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins 2005, Meindl 2002, Pennington 2013, Jimenez 2009, Plaskocinska 2016). These data do not allow any conclusion about variant significance. Several co-occurrences with other pathogenic variants have been reported (in UMD: BRCA1 c.81_4986del (p.Cys27X), BRCA2 c.8023A>G (p.Ile2675Val), BRCA2 c.5909C>A (p.Ser1970X); Jimenez 2009: BRCA1 c.1570delG (p.Ala524Glnfs); and in an internal sample: BRCA2 c.1813dupA (p.Ile605fsX11)), 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 have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as Likely Benign (2x) or VUS (4x). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761121 SCV000891037 uncertain significance B lymphoblastic leukemia lymphoma with hyperdiploidy 2016-10-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131272 SCV000902901 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659751 SCV001878192 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) RCV000031001 SCV000053593 likely benign Breast-ovarian cancer, familial 1 2012-07-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031001 SCV000144128 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355803 SCV001550791 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Leu512Phe variant was identified in 4 of 2744 proband chromosomes (frequency: 0.001) from German, American and British individuals or families with HBOC or endometrial cancer (Meindl_2002_11802209, Pennington_2012_22811390, Plaskocinska_2016_27208206). The variant was also identified in dbSNP (ID: rs41286294) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by GeneDx, Invitae and SCRP; and uncertain significance by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Quest Diagnostics Nichols Institute San Juan Capistrano, Counsyl and BIC ), Clinvitae (5x), Genesight-COGR (1x), LOVD 3.0 (1x ), UMD-LSDB (9x as class 2 - likely neutral, co-occurring with pathogenic BRCA2 variants (c.8023A>G, p.Ile2675Val and c.5909C>A, p.Ser1970X)), and BIC Database (6x with unknown clinical importance, classification pending); and was not identified in Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276590 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 11 of 126252 chromosomes (freq: 0.00009), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Leu512Phe 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 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. 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.