Submissions for variant NM_000059.4(BRCA2):c.7051G>T (p.Ala2351Ser)

dbSNP: rs80358930

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469511	SCV000549638	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2351 of the BRCA2 protein (p.Ala2351Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 409502). 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	RCV001025974	SCV001188267	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-30	criteria provided, single submitter	clinical testing	The p.A2351S variant (also known as c.7051G>T), located in coding exon 13 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7051. The alanine at codon 2351 is replaced by serine, an amino acid with similar properties. 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. This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV001529264	SCV002521976	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 7279G>T; This variant is associated with the following publications: (PMID: 32377563, 29884841)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001529264	SCV004220541	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer and healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/250694 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004000813	SCV004844357	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2351 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=0.884 (95%CI 0.055 to 14.136); p-value=1; Leiden Open Variation Database DB-ID BRCA2_001274) (PMID: 33471991). This variant has been identified in 1/250694 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529264	SCV001742415	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529264	SCV001928327	likely benign	not provided		no assertion criteria provided	clinical testing