ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1342C>T (p.His448Tyr) (rs786203578)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166956 SCV000217777 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239192 SCV000296413 uncertain significance Breast-ovarian cancer, familial 1 2016-06-10 criteria provided, single submitter clinical testing
Invitae RCV000549550 SCV000635792 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 448 of the BRCA1 protein (p.His448Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with prostate cancer (PMID: 15447980). ClinVar contains an entry for this variant (Variation ID: 187241). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001192525 SCV001360727 uncertain significance not specified 2019-10-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1342C>T (p.His448Tyr) results in a conservative amino acid change located in the BRCA1, Serine-rich domain (IPRO25994) of 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 8e-06 in 250878 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1342C>T has been reported in the literature in a sequencing study of individuals affected with Prostate cancer where it was reportedly identified among some unaffected males in one bileneal family (Zuhlke_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA2 c.7180A>T, p.Arg2394Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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.