Submissions for variant NM_000059.4(BRCA2):c.3835A>G (p.Asn1279Asp)

gnomAD frequency: 0.00002  dbSNP: rs80358626

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130851	SCV000185749	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.N1279D variant (also known as c.3835A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3835. The asparagine at codon 1279 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000657036	SCV000279382	uncertain significance	not provided	2017-08-16	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3835A>G at the cDNA level, p.Asn1279Asp (N1279D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 4063A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1279Asp was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn1279Asp occurs at a position that is not conserved and is located within the RAD51 binding domain (Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Asn1279Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657036	SCV000600565	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 35264596 (2022)). This variant is also reported to be located in a region of the BRCA2 gene that tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000026 (3/116358 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.
Counsyl	RCV000077314	SCV000785436	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-08-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000709309	SCV000838789	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763886	SCV000894821	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
Color Diagnostics, LLC DBA Color Health	RCV000130851	SCV000903290	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000077314	SCV001139074	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000709309	SCV001536340	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000221261	SCV001748799	uncertain significance	not specified	2021-07-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3835A>G (p.Asn1279Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 215842 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3835A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. The variant has been reported in one individual in the Breast Cancer Information Core (BIC) database and in one individual diagnosed with brain cancer (Jones_2015). Nine ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130851	SCV003846907	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).
Sharing Clinical Reports Project (SCRP)	RCV000077314	SCV000109111	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-10-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077314	SCV000146304	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-07-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353872	SCV000591877	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn1279Asp was identified in dbSNP (ID: rs80358626) “With Uncertain significance allele”, and in the ClinVar database where it was classified with “uncertain” clinical significance by three submitters (Sharing Clinical Reports Project, derived from Myriad reports; BIC; Ambry Genetics). The variant was identified the Exome Aggregation Consortium (ExAC) database in 2 of 52506 European (Non-Finnish) individuals; this low number of observations is not is not substantive enough to determine the frequency of the variant in the general population and its relationship to disease. The variant was not identified in the literature, nor was it identified in any of the other databases searched. 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. The p.Asn1279 residue is not conserved in mammals and 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. 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.