ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5612G>A (p.Ser1871Asn) (rs80358782)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588661 SCV000883485 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing The BRCA2 c.5612G>A; p.Ser1871Asn variant (rs80358782) has been reported in individuals with early-onset prostate cancer or breast cancer (Edwards 2003, El Saghir 2015, Lee 2008). This variant is reported multiple times in ClinVar as uncertain (Variation ID: 51891), and observed in general population databases with overall allele frequencies of 0.02 percent (1/5008 alleles, 1000 Genomes Project), and 0.006 percent (17/273156 alleles, Genome Aggregation Database). The serine at codon 1871 is weakly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, due to the limited information regarding p.Ser1871Asn, its clinical significance in uncertain at this time. REFERENCES Link to ClinVar database for p.Ser1871Asn: https://www.ncbi.nlm.nih.gov/clinvar/variation/51891/ Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan;72(1):1-12. El Saghir NS et al. BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer. Oncologist. 2015 Apr;20(4):357-64. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19.
Ambry Genetics RCV000130705 SCV000185592 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077355 SCV000146644 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000130705 SCV000903134 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Counsyl RCV000077355 SCV000785315 uncertain significance Breast-ovarian cancer, familial 2 2017-07-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588661 SCV000225159 uncertain significance not provided 2015-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000588661 SCV000278862 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5612G>A at the cDNA level, p.Ser1871Asn (S1871N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 5840G>A. This variant was observed in at least two individuals with breast cancer and an individual with early-onset prostate cancer (Edwards 2003, Lee 2008, El Saghir 2015). BRCA2 Ser1871Asn was observed at an allele frequency of 0.071% (17/23,904) in individuals of African ancestry in large population cohorts (Lek 2016). BRCA2 Ser1871Asn is located within the RAD51 binding domain (Roy 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser1871Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588661 SCV000694883 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5612G>A (p.Ser1871Asn) variant located in BRCA2 repeat domain (via InterPro) involves the alteration of a non-conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 17/273156 control chromosomes, predominantly in the African cohort at a frequency of 0.000711 (17/23904). This frequency is comparable to the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000044695 SCV000072708 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1871 of the BRCA2 protein (p.Ser1871Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs80358782, ExAC 0.05%). This variant has been reported in individuals with prostate cancer and breast cancer (PMID: 12474142, 25777348). This variant is also known as c.5840G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 51891). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000044695 SCV000838817 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215831 SCV000600648 uncertain significance not specified 2016-09-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077355 SCV000109152 uncertain significance Breast-ovarian cancer, familial 2 2008-05-22 no assertion criteria provided clinical testing

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