Submissions for variant NM_000059.4(BRCA2):c.3887A>G (p.Asn1296Ser)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002366334	SCV002624289	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-27	criteria provided, single submitter	clinical testing	The p.N1296S variant (also known as c.3887A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3887. The asparagine at codon 1296 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002366334	SCV003848502	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403789	SCV004122587	uncertain significance	not specified	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3887A>G (p.Asn1296Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 192906 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3887A>G has been reported in the literature in a relative from a family with Ovarian or Breast Cancer before 50 years old, without strong evidence for causality (example, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25186627). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign/likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003645263	SCV004426848	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1296 of the BRCA2 protein (p.Asn1296Ser). This variant is not present in population databases (gnomAD no frequency). 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: 1735845). 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.
All of Us Research Program, National Institutes of Health	RCV004005646	SCV004837460	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1296 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 breast cancer (PMID: 25186627). 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.