Submissions for variant NM_000059.4(BRCA2):c.1133G>A (p.Ser378Asn)

dbSNP: rs1593892009

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001009962	SCV001170096	likely benign	Hereditary cancer-predisposing syndrome	2017-11-02	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001207859	SCV001379226	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-11	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 378 of the BRCA2 protein (p.Ser378Asn). 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. 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. ClinVar contains an entry for this variant (Variation ID: 818401). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
University of Washington Department of Laboratory Medicine, University of Washington	RCV001009962	SCV003849859	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321771	SCV004027400	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004480	SCV004824301	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 378 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: 33471991; Leiden Open Variation Database DB-ID BRCA2_007792). 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.
Fulgent Genetics, Fulgent Genetics	RCV005012441	SCV005634400	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-04-03	criteria provided, single submitter	clinical testing