ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9275A>T (p.Tyr3092Phe) (rs80359195)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167271 SCV000218113 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000167271 SCV000684047 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
GeneDx RCV000767170 SCV000566404 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9275A>T at the cDNA level, p.Tyr3092Phe (Y3092F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 9503A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr3092Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr3092Phe occurs at a position that is conserved across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Tyr3092Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000483136 SCV000918964 uncertain significance not specified 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9275A>T (p.Tyr3092Phe) results in a conservative amino acid change located in the BRCA2, OB3 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245422 control chromosomes. 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.9275A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) in BRCA2 have been reported by a clinical lab via ClinVar (variant not specified), providing supporting evidence for a benign role. Four 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.
Invitae RCV000560384 SCV000635732 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 3092 of the BRCA2 protein (p.Tyr3092Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is present in population databases (rs80359195, ExAC 0.009%). This variant has been observed in an individual with breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2 gene, which suggests that this c.9275A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 91522). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483136 SCV000600852 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077039 SCV000108836 uncertain significance Breast-ovarian cancer, familial 2 2007-01-29 no assertion criteria provided clinical testing

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