Submissions for variant NM_000059.4(BRCA2):c.3836A>G (p.Asn1279Ser)

dbSNP: rs1060502384

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474984	SCV000549500	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-29	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 1279 of the BRCA2 protein (p.Asn1279Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, as well as in unaffected individuals (PMID: 12552570, 25503501, 37415649). ClinVar contains an entry for this variant (Variation ID: 409423). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000509695	SCV000608052	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-15	criteria provided, single submitter	clinical testing	The p.N1279S variant (also known as c.3836A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3836. The asparagine at codon 1279 is replaced by serine, an amino acid with highly similar properties. In one study, this variant was reported in 1/40 Cypriot families with multiple cases of breast and ovarian cancer and 1/50 unrelated healthy Cypriots with no history of breast or ovarian cancer (Hadjisavvas A et al. Hum. Mutat. 2003 Feb;21(2):171; Hadjisavvas A et al. Cancer Genet. Cytogenet. 2004 Jun;151(2):152-6). This alteration was also previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6469 samples (12938 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000509695	SCV000910323	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1279 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 individuals affected with breast cancer (PMID: 12552570, 25503501, 37415649) and in an unaffected individual (PMID: 12552570). 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.
MGZ Medical Genetics Center	RCV003607287	SCV002579733	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465659	SCV002761156	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509695	SCV003846908	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).
GeneDx	RCV004591318	SCV005079855	uncertain significance	not provided	2023-10-03	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; Observed in individuals with breast and/or ovarian cancers (Hadjisavvas et al., 2003; Maxwell et al., 2015); This variant is associated with the following publications: (PMID: 31911673, 15172753, 29884841, 25503501, 12552570, 31853058, 32377563, 27527004, 35753294)
All of Us Research Program, National Institutes of Health	RCV004801999	SCV005424406	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1279 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 individuals affected with breast cancer (PMID: 12552570, 25503501, 37415649) and in an unaffected individual (PMID: 12552570). 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.