Submissions for variant NM_000059.4(BRCA2):c.8765G>A (p.Ser2922Asn)

gnomAD frequency: 0.00001  dbSNP: rs730881567

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656807	SCV000210483	uncertain significance	not provided	2017-10-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8765G>A at the cDNA level, p.Ser2922Asn (S2922N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 8993G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser2922Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ser2922Asn occurs at a position where amino acids with properties similar to Serine are tolerated across species 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 evidence, it is unclear whether BRCA2 Ser2922Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168175	SCV000218838	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2922 of the BRCA2 protein (p.Ser2922Asn). This variant is present in population databases (rs730881567, 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: 182254). 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	RCV000222266	SCV000274058	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-26	criteria provided, single submitter	clinical testing	The p.S2922N variant (also known as c.8765G>A), located in coding exon 21 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8765. The serine at codon 2922 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160156	SCV000919035	uncertain significance	not specified	2021-07-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8765G>A (p.Ser2922Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250506 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8765G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998451	SCV004841337	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2922 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 2/250506 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353947	SCV000592230	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ser2922Asn variant has not been previously reported in the literature. It has been previously reported in the CNPHI database as a VUS (https://www.cnphi-rcrsp.ca) but not in other public databases, and it has been previously been reported by our laboratory in one individual who met criteria for hereditary breast and ovarian cancer. The Ser2922 residue is conserved across mammals and lower species and computational analyses (SIFT) suggest that this variant may impact the protein function, but this information is not enough to assume pathogenicity. In summary, based on this limited amount of information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance (VUS).