Submissions for variant NM_000059.4(BRCA2):c.8824G>A (p.Ala2942Thr)

dbSNP: rs80359139

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045636	SCV000073649	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2942 of the BRCA2 protein (p.Ala2942Thr). This variant is present in population databases (rs80359139, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 52687). 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) performed at Invitae 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	RCV000129548	SCV000184328	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-29	criteria provided, single submitter	clinical testing	The p.A2942T variant (also known as c.8824G>A), located in coding exon 21 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8824. The alanine at codon 2942 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000483549	SCV000571442	uncertain significance	not provided	2018-04-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8824G>A at the cDNA level, p.Ala2942Thr (A2942T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 9052G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2942Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2942Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000114005	SCV000785244	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129548	SCV000906956	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2942 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 endometrial carcinoma in the literature (PMID: 26689913). This variant has been identified in 1/250826 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001235	SCV001158399	uncertain significance	not specified	2019-05-10	criteria provided, single submitter	clinical testing	The BRCA2 c.8824G>A; p.Ala2942Thr variant (rs80359139) is reported with uncertain significance in ClinVar (Variation ID: 52687). This variant is only observed in one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 2942 is highly conserved, but a protein likelihood algorithm specifically designed for BRCA2 missense variants, suggests this variant is tolerated (Karchin 2008). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Karchin R et al. Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203-16.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483549	SCV001470457	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004566855	SCV005059025	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114005	SCV000147468	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing