Submissions for variant NM_000059.4(BRCA2):c.3929C>T (p.Thr1310Ile)

dbSNP: rs730881528

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160071	SCV000210326	uncertain significance	not provided	2014-04-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3929C>T at the cDNA level, p.Thr1310Ile (T1310I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr1310Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Thr1310Ile occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr1310Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509663	SCV000608138	likely benign	Hereditary cancer-predisposing syndrome	2024-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000509663	SCV000688838	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1310 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 BRCA2-related disorders 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	RCV001223495	SCV001395647	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-03	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 1310 of the BRCA2 protein (p.Thr1310Ile). 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: 182205). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509663	SCV003848540	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).
All of Us Research Program, National Institutes of Health	RCV003998443	SCV004845245	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1310 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 BRCA2-related disorders 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.