ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5414A>G (p.Asn1805Ser) (rs80358765)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044656 SCV000072669 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000590661 SCV000108625 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5414A>G at the cDNA level, p.Asn1805Ser (N1805S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant has been previously published as BRCA2 5642A>G. BRCA2 Asn1805Ser has been reported in several individuals with breast or ovarian cancer as well as in a control patient in a separate study (Wagner 1999, Soegaard 2008, Pal 2015, Encinas 2018). This variant was observed at an allele frequency of 0.038% (9/24,018) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may create a cryptic splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Asn1805Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000131487 SCV000186475 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-31 criteria provided, single submitter clinical testing The p.N1805S variant (also known as c.5414A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5414. The asparagine at codon 1805 is replaced by serine, an amino acid with highly similar properties. This alteration was reported in one control allele in an individual of African descent from a cohort including 332 globally heterogeneous chromosomes (Wagner TM et al. Hum. Mol. Genet. 1999 Mar;8:413-23). This alteration was reported in a cohort of patients diagnosed with early-onset breast cancer and self-reported to have African American and/or Afro-Caribbean, and/or other/mixed descent; the authors classified this alteration as "suspected benign" (Pal T et al. Cancer. 2015 Dec;121:4173-80). This alteration was also reported in 1 of 445 individuals with invasive epithelial ovarian cancer from Denmark (Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7) as well as two individuals with breast cancer from Brazil (Encinas G et al. Oncotarget. 2018 Apr;9:22460-22479). Of note, this alteration is also designated as 5642A>G in published literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000113427 SCV000296612 uncertain significance Breast-ovarian cancer, familial 2 2016-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855580 SCV000694867 uncertain significance not specified 2020-10-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5414A>G (p.Asn1805Ser) 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 6.4e-05 in 282762 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.5414A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as in control population (Soegaard_2008, Wagner_1999, Encinas_2018, Pal_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. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x), likely benign (2x) and benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000113427 SCV000784936 uncertain significance Breast-ovarian cancer, familial 2 2017-02-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000590661 SCV000885113 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590661 SCV000889068 likely benign not provided 2020-01-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131487 SCV000903212 likely benign Hereditary cancer-predisposing syndrome 2015-08-14 criteria provided, single submitter clinical testing
Mendelics RCV000113427 SCV001139113 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113427 SCV001270128 uncertain significance Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001112467 SCV001270129 uncertain significance Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113427 SCV000146610 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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