ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6761T>A (p.Phe2254Tyr) (rs786202915)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165980 SCV000216738 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-01 criteria provided, single submitter clinical testing The p.F2254Y variant (also known as c.6761T>A<span style="background-color:initial">), located in coding exon 10 of the BRCA2<span style="background-color:initial"> gene, results from a T to A substitution at nucleotide position 6761. The phenylalanine at codon 2254 is replaced by tyrosine, an amino acid with highly similar properties. <span style="background-color:initial">This amino acid position is 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.
Counsyl RCV000238769 SCV000488286 uncertain significance Breast-ovarian cancer, familial 2 2016-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000587444 SCV000566695 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6761T>A at the cDNA level, p.Phe2254Tyr (F2254Y) at the protein level, and results in the change of a Phenylalanine to a Tyrosine (TTT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 6989T>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Phe2254Tyr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Phe2254Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000479534 SCV000592073 likely benign not specified 2012-10-01 criteria provided, single submitter clinical testing
Invitae RCV000530254 SCV000635529 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with tyrosine at codon 2254 of the BRCA2 protein (p.Phe2254Tyr). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in trans (on the opposite chromosome) from a pathogenic variant in BRCA2 in an individual affected with breast cancer (Invitae). Considering that biallelic pathogenic variants are expected to be found in an individual affected with Fanconi anemia, this evidence indicates that this variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 186392). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Color RCV000165980 SCV000683808 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000479534 SCV000694994 uncertain significance not specified 2020-08-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6761T>A (p.Phe2254Tyr) 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 was absent in 251266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6761T>A in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587444 SCV000887890 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735581 SCV000863719 uncertain significance Breast and/or ovarian cancer no assertion criteria provided clinical testing

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