Submissions for variant NM_000059.4(BRCA2):c.2315C>T (p.Thr772Ile)

dbSNP: rs1064794522

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479708	SCV000569363	uncertain significance	not provided	2017-01-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2315C>T at the cDNA level, p.Thr772Ile (T772I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 2543C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr772Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr772Ile occurs at a position that is not conserved and is not located in a known functional domain. 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 Thr772Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000580617	SCV000683477	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 772 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321251	SCV001512073	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-08	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 772 of the BRCA2 protein (p.Thr772Ile). 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: 420503). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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	RCV000580617	SCV002734379	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The p.T772I variant (also known as c.2315C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2315. The threonine at codon 772 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000580617	SCV003848220	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).