Submissions for variant NM_000059.4(BRCA2):c.5498A>G (p.Asn1833Ser)

gnomAD frequency: 0.00006  dbSNP: rs587782601

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131959	SCV000187016	likely benign	Hereditary cancer-predisposing syndrome	2017-05-18	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.
Invitae	RCV000206165	SCV000261215	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	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 1833 of the BRCA2 protein (p.Asn1833Ser). This variant is present in population databases (rs587782601, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142634). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
GeneDx	RCV000985250	SCV000517306	likely benign	not provided	2020-03-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985250	SCV000600644	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in a family with hereditary breast and ovarian cancer (HBOC) syndrome (PMID: 30254663 (2018)). This variant was found to co-occur with a pathogenic variant in BRCA1 in one individual (Quest internal data). The frequency of this variant in the general population, 0.00016 (4/24840 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.
Color Diagnostics, LLC DBA Color Health	RCV000131959	SCV000906108	likely benign	Hereditary cancer-predisposing syndrome	2018-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432115	SCV000919028	uncertain significance	not specified	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5498A>G (p.Asn1833Ser) 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 8e-06 in 250496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5498A>G has been reported in the literature as a VUS in at-least one individual affected with Hereditary Breast and/or Ovarian Cancer (example, Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.4327C>T, p.Arg1443Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; likely benign, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000432115	SCV001158489	uncertain significance	not specified	2019-05-15	criteria provided, single submitter	clinical testing	The BRCA2 c.5498A>G; p.Asn1833Ser variant (rs587782601) is reported in the literature in a family affected with breast and/or ovarian cancer, although its clinical significance was not determined in this study (Zuntini 2018). This variant is found on only four chromosomes (4/24840 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 142634). The asparagine at codon 1833 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Asn1833Ser variant is uncertain at this time. References: Zuntini R et al. Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? Front Genet. 2018 Sep 11;9:378.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131959	SCV003848866	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).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444206	SCV004171452	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-22	criteria provided, single submitter	clinical testing	The BRCA2 c.5498A>G (p.Asn1833Ser) missense change a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 30254663). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV003444206	SCV004228413	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)