Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000205538 | SCV000260491 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-09-18 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3411 of the BRCA2 protein (p.Thr3411Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 220161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. 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. |
| Ambry Genetics | RCV001017040 | SCV001178063 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-23 | criteria provided, single submitter | clinical testing | The p.T3411I variant (also known as c.10232C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 10232. The threonine at codon 3411 is replaced by isoleucine, 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, |
RCV000502836 | SCV000592320 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA2 p.Thr3411Ile variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (14 March 2016), Fanconi Anemia Mutation Database, COSMIC, MutDB, ARUP Laboratories BRCA Mutations Database, GeneInsight COGR, BIC or BRCA Share UMD. The variant was identified in ClinVar and Clinvitae databases by Invitae and classified as uncertain significance. The p.Thr3411 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; however, this information is not predictive enough to rule out pathogenicity. The c.10232C>T (p.Thr3411Ile) variant occurs at the 3’ terminal end location of the BRCA2 gene, which is suggested to be a possibly dispensable part of the gene (Borg 2010) and therefore unlikely to have a deleterious effect. 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. |