Submissions for variant NM_000059.4(BRCA2):c.7121A>G (p.Asn2374Ser)

gnomAD frequency: 0.00001  dbSNP: rs1379054137

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575236	SCV000661374	likely benign	Hereditary cancer-predisposing syndrome	2016-10-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000575236	SCV000689031	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804735	SCV000944658	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-29	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 2374 of the BRCA2 protein (p.Asn2374Ser). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 479361). 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.
GeneDx	RCV001591321	SCV001824861	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, but also in unaffected controls (Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7349A>G; This variant is associated with the following publications: (PMID: 32980694, 32377563, 29884841, 30287823)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591321	SCV002774475	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003233747	SCV003930444	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the BRCA2 gene (c.7121A>G). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2374 of the BRCA2 protein (p.Asn2374Ser). This variant is present in population databases (gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 32980694, 27535533, 30287823). ClinVar contains an entry for this variant (Variation ID: 479361). Computational prediction is benign based on PolyPhen, SIFT, BayesDel_addAF, DANN, FATHMM-MKL, M-CAP, MVP , EIGEN, MutationTaster and PrimateAI. 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.