Submissions for variant NM_000059.4(BRCA2):c.8180C>G (p.Ala2727Gly)

dbSNP: rs879255468

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469799	SCV000549522	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2727 of the BRCA2 protein (p.Ala2727Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of pancreatic cancer (PMID: 31432501). ClinVar contains an entry for this variant (Variation ID: 252853). 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.
GeneDx	RCV000483895	SCV000566582	uncertain significance	not provided	2015-05-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8180C>G at the cDNA level, p.Ala2727Gly (A2727G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8408C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2727Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala2727Gly occurs at a position that is conserved in mammals and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ala2727Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000565073	SCV000661395	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.A2727G variant (also known as c.8180C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8180. The alanine at codon 2727 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was identified in a patient diagnosed with intraductal papillary mucinous neoplasms at 65 who had a first degree relative with pancreatic adenocarcinoma (Schwartz M et al. Clin Genet, 2019 12;96:579-584). This amino acid position is not well conserved in available vertebrate species, and glycine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health	RCV000565073	SCV000905231	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 2727 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 an individual affected with intraductal papillary mucinous neoplasms with a family history of pancreatic cancer (PMID: 31432501). 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.
Sharing Clinical Reports Project (SCRP)	RCV000238976	SCV000297456	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-09-03	no assertion criteria provided	clinical testing