ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1703C>T (p.Pro568Leu) (rs80356910)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
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) RCV000083171 SCV001161489 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 = 8.19E-06
Invitae RCV001079198 SCV000075577 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131307 SCV000186279 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing Other data supporting benign classification
GeneDx RCV000443568 SCV000515690 likely benign not specified 2017-10-27 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.
Genetic Services Laboratory, University of Chicago RCV000443568 SCV000593689 uncertain significance not specified 2017-03-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131307 SCV000682977 likely benign Hereditary cancer-predisposing syndrome 2017-03-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588961 SCV000698882 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1703C>T (p.Pro568Leu) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant has been reported in several HBOC patients without strong evidence for causality and is absent in 121082 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases provided conflicting classifications for this variant ranging from VUS to Benign without evidence to independently evaluate. Additional data needed to evaluate this variant with confidence. Taken together, the variant is classified as a variant of uncertain significance (VUS) until new information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588961 SCV000888844 likely benign not provided 2018-01-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000083171 SCV001287419 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP) RCV000083171 SCV000115245 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083171 SCV000144161 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 RCV000083171 SCV000591348 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Pro568Leu variant was identified in the literature in at least two individuals or families with early onset or hereditary breast cancer (Haffty 2009, Judkins 2005); however control chromosomes from healthy individuals were not assessed in these studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs80356910) “With uncertain significance allele”, the BIC database (8X with unknown clinical importance), LOVD, and UMD (1X as a class 3-UV variant). The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) along with submission by Invitae and Ambry stating unknown significance. The p.Pro568 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In silico studies using evolutionary conservation analysis predict this variant to have no effect on the protein (Fleming 2003) or were inconclusive (Burk-Herrick 2005). In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, it should be noted that all of the above in silico predictions are not predictive enough to rule out pathogenicity. 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.