Submissions for variant NM_000059.4(BRCA2):c.8704G>A (p.Ala2902Thr)

dbSNP: rs1555288163

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549352	SCV000635683	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-15	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 2902 of the BRCA2 protein (p.Ala2902Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 462492). 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.
Color Diagnostics, LLC DBA Color Health	RCV000777215	SCV000912906	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2902 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 been reported in two families suspected of being affected with hereditary breast and ovarian cancer (PMID: 30254663; doi.org/10.1515/tjb-2019-0424). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781131	SCV000918985	uncertain significance	not specified	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.8704G>A (p.Ala2902Thr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 246134 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. The variant has been reported in one database with a classification of VUS. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV000777215	SCV001179409	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-22	criteria provided, single submitter	clinical testing	The p.A2902T variant (also known as c.8704G>A), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8704. The alanine at codon 2902 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was identified in 1/1045 patients with breast and/or ovarian cancer who fulfilled established BRCA1/2 genetic testing criteria (Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Department of Medical and Surgical Sciences, University of Bologna	RCV003483662	SCV004228453	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)