ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7081C>T (p.His2361Tyr) (rs786203493)

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 RCV000166818 SCV000217632 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000589542 SCV000618051 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7081C>T at the cDNA level, p.His2361Tyr (H2361Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 7309C>T. This variant was observed in cell-free DNA from a patient with breast cancer (Liang 2016). BRCA2 His2361Tyr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His2361Tyr occurs at a position that is not conserved and is located in the FANCD2 binding domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 His2361Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589542 SCV000695035 uncertain significance not provided 2016-05-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7081C>T variant affects a non-conserved nucleotide, resulting in an amino acid change from His to Tyr. 3/5 in-silico tools predict this variant to be damaging. This variant was not found in 121234 control chromosomes. In addition, one clinical laboratory classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals in the literature, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000804009 SCV000943899 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 2361 of the BRCA2 protein (p.His2361Tyr). 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 187126). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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.