Submissions for variant NM_000059.4(BRCA2):c.7772A>G (p.Asn2591Ser)

dbSNP: rs80359006

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240696	SCV000265961	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000677097	SCV000803158	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000677097	SCV001189247	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-16	criteria provided, single submitter	clinical testing	The p.N2591S variant (also known as c.7772A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7772. The asparagine at codon 2591 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, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341578	SCV001535458	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-09	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 2591 of the BRCA2 protein (p.Asn2591Ser). 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: 52407). 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%. Studies have shown that this missense change does not affect mRNA splicing (PMID: 29881398). 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.
Sema4, Sema4	RCV000677097	SCV002531883	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271389	SCV002556187	uncertain significance	not specified	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7772A>G (p.Asn2591Ser) results in a conservative amino acid change located in the breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251432 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7772A>G has been reported in the literature in a tumor from an individual with breast cancer, however it was not found in the germline of this individual (Zhong_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was predicted to have a neutral effect on protein function by a protein likelihood ratio model (Karchin_ 2008) and it was not found to impact splicing (Fraile-Bethencourt_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113816	SCV000147179	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing