ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4654T>C (p.Tyr1552His) (rs1265352633)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532651 SCV000635985 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1552 of the BRCA1 protein (p.Tyr1552His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer and cutaneous malignant melanoma (PMID: 22713736, 29036293). This variant is also known as 4773T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 433716). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The histidine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758836 SCV000887705 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765359 SCV000896624 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776618 SCV000912236 likely benign Hereditary cancer-predisposing syndrome 2017-10-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000776618 SCV001184632 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing The p.Y1552H variant (also known as c.4654T>C), located in coding exon 13 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4654. The tyrosine at codon 1552 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504104 SCV000591531 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Tyr1552His variant was identified by Jalkh (2012) in a Lebanese individual with breast cancer. The variant was also identified in UMD (2X as an unclassified variant); in one of these samples it was found in co-occurrence with a pathogenic BRCA1 mutation (c.4358_4484del (p.Ala1453GlyfsX10)), increasing the likelihood that the p.Tyr1552His variant does not have clinical significance. 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. The p.Ala469Thr 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. 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 unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735520 SCV000863658 likely benign Breast and/or ovarian cancer 2013-10-03 no assertion criteria provided clinical testing

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.