ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8262T>G (p.His2754Gln) (rs587776472)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000144193 SCV000489647 uncertain significance Breast-ovarian cancer, familial 2 2016-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000483045 SCV000571256 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8262T>G at the cDNA level, p.His2754Gln (H2754Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAT>CAG). Using alternate nomenclature, this variant would be defined as BRCA2 8490T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His2754Gln 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 Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 His2754Gln occurs at a position that is not conserved and is located in 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 His2754Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575580 SCV000661431 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000637765 SCV000759242 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 2754 of the BRCA2 protein (p.His2754Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 156176). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Sharing Clinical Reports Project (SCRP) RCV000144193 SCV000189266 uncertain significance Breast-ovarian cancer, familial 2 2011-03-01 no assertion criteria provided clinical testing

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