Submissions for variant NM_000059.4(BRCA2):c.3962A>G (p.Asp1321Gly)

gnomAD frequency: 0.00002  dbSNP: rs80358645

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212233	SCV000210327	uncertain significance	not provided	2015-02-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3962A>G at the cDNA level, p.Asp1321Gly (D1321G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 4190A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp1321Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp1321Gly occurs at a position that is moderately conserved across species and is not located in a known functional domain (UniProt, Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asp1321Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000571707	SCV000668640	likely benign	Hereditary cancer-predisposing syndrome	2024-11-11	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	RCV000571707	SCV000683593	likely benign	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320562	SCV001511352	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-20	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212233	SCV002010374	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267811	SCV002550329	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571707	SCV003848559	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).
All of Us Research Program, National Institutes of Health	RCV000113252	SCV004845246	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212233	SCV005875505	likely benign	not provided	2024-06-03	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113252	SCV000146346	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113252	SCV004243617	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing