Submissions for variant NM_000059.4(BRCA2):c.5938A>C (p.Thr1980Pro)

dbSNP: rs55877890

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531811	SCV000635483	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1980 of the BRCA2 protein (p.Thr1980Pro). 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: 462394). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000568300	SCV000666126	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The p.T1980P variant (also known as c.5938A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5938. The threonine at codon 1980 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568300	SCV000911764	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1980 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007408). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568300	SCV003850800	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).
Genetics and Molecular Pathology, SA Pathology	RCV003447541	SCV004175366	uncertain significance	Fanconi anemia complementation group D1	2023-01-12	criteria provided, single submitter	clinical testing	The BRCA2 c.5938A>C variant is classified as VUS (PM2, PP3) The BRCA2 c.5938A>C variant is a single nucleotide change in exon 11/27 of the BRCA2 gene, which is predicted to change the amino acid threonine at position 1980 in the protein to proline. This variant is absent from population databases (PM2). This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007408) Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs55877890) and has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 462394). It has not been reported in HGMD.
All of Us Research Program, National Institutes of Health	RCV003999064	SCV004846674	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1980 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007408). 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.