ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5612G>A (p.Ser1871Asn) (rs80358782)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044695 SCV000072708 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130705 SCV000185592 likely benign Hereditary cancer-predisposing syndrome 2019-12-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588661 SCV000600648 likely benign not provided 2020-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000215831 SCV000694883 uncertain significance not specified 2020-10-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5612G>A (p.Ser1871Asn) 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 6.1e-05 in 278618 control chromosomes, predominantly at a frequency of 0.00069 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with prostate cancer and breast cancer (Edwards_2003, Lee_2008, El Saghir_2015). These reports do 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. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (8x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000077355 SCV000785315 uncertain significance Breast-ovarian cancer, familial 2 2017-07-05 criteria provided, single submitter clinical testing
Mendelics RCV000044695 SCV000838817 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
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.
Color Health, Inc RCV000130705 SCV000903134 likely benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000077355 SCV001139117 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000077355 SCV000146644 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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