Submissions for variant NM_000059.4(BRCA2):c.2908G>A (p.Asp970Asn)

gnomAD frequency: 0.00001  dbSNP: rs397507295

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129877	SCV000184694	likely benign	Hereditary cancer-predisposing syndrome	2023-12-20	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	RCV000196636	SCV000254177	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000588181	SCV000279290	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3136G>A; This variant is associated with the following publications: (PMID: 27767231, 28726806)
Color Diagnostics, LLC DBA Color Health	RCV000129877	SCV000683510	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 970 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 3/248956 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588181	SCV000694645	uncertain significance	not provided	2016-02-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763884	SCV000894819	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735533	SCV000901103	uncertain significance	Breast and/or ovarian cancer	2017-06-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129877	SCV003850224	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588181	SCV004219559	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	The BRCA2 c.2908G>A (p.Asp970Asn) variant has been reported in the published literature in an individual with ovarian cancer (PMID: 27767231 (2017)) and is described as being located in a region of BRCA2 that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000027 (3/112900 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004803013	SCV004845080	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 970 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/248956 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000031387	SCV000053992	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000220683	SCV000591834	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp970Asn variant was not identified in the literature. The variant was identified in dbSNP (ID: rs397507295) “With uncertain significance allele”, the Clinvitae database (3X as with uncertain significance), the ClinVar database (classified as an uncertain significance variant by Ambry Genetics, Invitae and SCRP), and the GeneInsight COGR database (as an unclassified variant). The variant was also found in the Exome Aggregation Consortium (ExAC) database in 1 of 66340 European (Non-Finnish) individuals (frequency: 1.51E-05) although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified by our laboratory in 5 individuals with hereditary breast and ovarian cancer. The variant was not found in the following databases: NHLBI Exome Sequencing Project (Exome Variant Server), LOVD, ARUP Laboratories BRCA Mutations Database (classification), COSMIC, the BIC database, and UMD. The p.Asp970 residue is not conserved in mammals, increasing the likelihood that this variant does not have clinical significance. In addition, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735533	SCV000863671	uncertain significance	Breast and/or ovarian cancer	2013-02-28	no assertion criteria provided	clinical testing