Submissions for variant NM_000059.4(BRCA2):c.2758C>A (p.Pro920Thr)

dbSNP: rs397507293

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469857	SCV000549505	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 920 of the BRCA2 protein (p.Pro920Thr). This variant is present in population databases (rs397507293, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 16875939). This variant is also known as 2986C>A. ClinVar contains an entry for this variant (Variation ID: 37800). 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.
Counsyl	RCV000031381	SCV000785767	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776350	SCV000911717	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 920 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with breast cancer (PMID:16875939). This variant has been identified in 1/250768 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.
Ambry Genetics	RCV000776350	SCV001177476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.P920T variant (also known as c.2758C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 2758. The proline at codon 920 is replaced by threonine, an amino acid with highly similar properties. This alteration was identified in a proband of a family with four cases of breast cancer from a cohort of 350 Swiss breast and ovarian cancer families (Maillet P et al, Cancer Genet. Cytogenet. 2006 Aug; 169(1):62-8). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000776350	SCV003850112	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).
GeneDx	RCV001355877	SCV003923359	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Observed in an individual with a personal and family history of breast cancer (Maillet et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2986C>A; This variant is associated with the following publications: (PMID: 23929434, 16875939)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005229837	SCV005872767	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031381	SCV000053986	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-01-21	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355877	SCV001550890	uncertain significance	not provided		no assertion criteria provided	clinical testing