ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6293C>T (p.Ser2098Phe) (rs80358867)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044890 SCV000072903 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-01 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 2098 of the BRCA2 protein (p.Ser2098Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs80358867, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 23961350, 28477318). This variant is also known as 6521C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52048). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000222689 SCV000277628 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-08 criteria provided, single submitter clinical testing The p.S2098F variant (also known as c.6293C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6293. The serine at codon 2098 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In one study, this variant was detected in 1/134 non-Ashkenazi Jewish Argentinean breast and/or ovarian cancer patients (Solano AR et al. Springerplus. 2012 Sep 25;1:20). It was also detected in one Spanish hereditary breast/ovarian cancer family (Gabaldó Barrios X et al. Fam. Cancer. 2017 Oct;16(4):477-489). In a study of whole exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This amino acid position is not well 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.
GeneDx RCV000656797 SCV000321474 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6293C>T at the cDNA level, p.Ser2098Phe (S2098F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 6521C>T or 6749C>T. This variant has been observed in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Solano 2012, Gabald? Barrios 2017). BRCA2 Ser2098Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ser2098Phe is not located in a known functional domain. 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 Ser2098Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656797 SCV000600689 uncertain significance not provided 2019-02-04 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000222689 SCV000679721 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Counsyl RCV000113560 SCV000785248 uncertain significance Breast-ovarian cancer, familial 2 2017-06-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000222689 SCV000903293 likely benign Hereditary cancer-predisposing syndrome 2017-03-06 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113560 SCV000146811 uncertain significance Breast-ovarian cancer, familial 2 2006-07-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355427 SCV001550309 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser2098Phe variant was identified in 2 of 1362 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Argentinian and Spanish ethnicity (Galbaldo 2017, Solano_2012,). The variant was also identified in dbSNP (ID: rs80358867) as ” with uncertain significance allele”; in ClinVar and Clinvitae databases with uncertain significance by Ambry Genetics, GeneDx, Quest Diagnostics Nichols Institute San Juan Capitstrano, Institute for Biomarker Research, Medical Diagnostic Laboratories, Invitae and Breast Cancer Information Core. The variant was further identified in the LOVD 3.0 database 1X (frequency: 0.0003), and in the BIC database 2X with unknown classification. The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 4 of 240210 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 15138 chromosomes (freq: 0.0001), European Non-Finnish in 2 of 109762 chromosomes (freq: 0.00002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser2098 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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