Submissions for variant NM_000059.4(BRCA2):c.8782G>T (p.Ala2928Ser)

gnomAD frequency: 0.00001  dbSNP: rs587781762

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129984	SCV000184808	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	The p.A2928S variant (also known as c.8782G>T), located in coding exon 21 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8782. The alanine at codon 2928 is replaced by serine, an amino acid with similar properties. This amino acid position is highly 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	RCV000479709	SCV000564800	uncertain significance	not provided	2016-10-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8782G>T at the cDNA level, p.Ala2928Ser (A2928S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant, also known as BRCA2 9010G>T using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2928Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2928Ser occurs at a position that is conserved among mammals and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ala2928Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544583	SCV000635692	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-09	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 2928 of the BRCA2 protein (p.Ala2928Ser). This variant is present in population databases (rs587781762, gnomAD 0.007%). 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: 141459). 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	RCV000129984	SCV001351220	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2928 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.102 and 1.318, respectively (PMID: 31131967). This variant has been identified in 1/31394 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.
All of Us Research Program, National Institutes of Health	RCV004804143	SCV004846071	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 2928 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31394 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.
Baylor Genetics	RCV004567101	SCV005059125	uncertain significance	Familial cancer of breast	2023-12-30	criteria provided, single submitter	clinical testing