Submissions for variant NM_000059.4(BRCA2):c.5503A>G (p.Asn1835Asp)

gnomAD frequency: 0.00005  dbSNP: rs80358771

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044672	SCV000072685	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1835 of the BRCA2 protein (p.Asn1835Asp). This variant is present in population databases (rs80358771, gnomAD 0.02%). This missense change has been observed in individual(s) with breast/ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 51873). 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 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	RCV000213098	SCV000276446	likely benign	Hereditary cancer-predisposing syndrome	2018-10-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000220592	SCV000279751	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5731A>G; This variant is associated with the following publications: (PMID: 25348012, 21120943, 32377563, 29884841, 31911673)
Color Diagnostics, LLC DBA Color Health	RCV000213098	SCV000903957	likely benign	Hereditary cancer-predisposing syndrome	2017-02-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000851	SCV001157925	uncertain significance	not specified	2018-10-09	criteria provided, single submitter	clinical testing	The BRCA2 c.5503A>G; p.Asn1835Asp variant (rs80358771), is reported in the literature in at least one individual affected with breast cancer (Caux-Moncoutier 2011). This variant is reported in ClinVar (Variation ID: 51873), and is found in the African population with an allele frequency of 0.02% (3/15,268 alleles) in the Genome Aggregation Database. The asparagine at codon 1835 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Asn1835Asp variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000851	SCV001361907	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5503A>G (p.Asn1835Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250144 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5503A>G has been reported in the literature in an individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Caux-Moncoutier_2011). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220592	SCV002046090	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00025 (4/16120 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a variant of uncertain significance in individuals with suspected hereditary breast and/or ovarian cancer syndrome (PMIDs: 21120943 (2011), 30630528 (2019), and 29884841 (2019)). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000213098	SCV003848870	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).
PreventionGenetics, part of Exact Sciences	RCV003415792	SCV004117955	uncertain significance	BRCA2-related condition	2022-11-06	criteria provided, single submitter	clinical testing	The BRCA2 c.5503A>G variant is predicted to result in the amino acid substitution p.Asn1835Asp. This variant has been reported as uncertain significance in a cohort of individuals with a personal and/or family history of breast cancer (Table S2, Caux-Moncoutier et al. 2011. PubMed ID: 21120943). It has also been reported in an individual with breast cancer from the Breast Information Core (BIC) database (https://research.nhgri.nih.gov/bic/, Accession ID: 8143, Szabo et al. 2000. PubMed ID: 10923033). This variant is reported in 5 of ~250,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/13-32913995-A-G) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/51873/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113440	SCV000146626	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-11-25	no assertion criteria provided	clinical testing