Submissions for variant NM_000059.4(BRCA2):c.2348T>C (p.Val783Ala)

dbSNP: rs768143929

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564881	SCV000661169	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing	The p.V783A variant (also known as c.2348T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2348. The valine at codon 783 is replaced by alanine, an amino acid with similar properties. This variant was detected in the germline of patient with Sertoli-Leydig cell tumor and called a variant of unknown significance; however, this patient was also found to have a pathogenic germline mutation in the DICER1 gene (Cowan M et al. Gynecol Oncol Rep, 2018 Aug;25:94-97). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696795	SCV000825374	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564881	SCV000906638	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 783 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 and has been reported in 2 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007939). This variant has been identified in 2/250824 chromosomes 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	RCV000564881	SCV003848247	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	RCV003999529	SCV004847045	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 783 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 and has been reported in 2 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007939). This variant has been identified in 2/250824 chromosomes 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.
GeneDx	RCV004721446	SCV005327621	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	Observed in an individual with embryonal rhabdomyosarcoma (PMID: 30014022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 2576T>C; This variant is associated with the following publications: (PMID: 30014022)