ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5961G>T (p.Gln1987His) (rs387907575)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480427 SCV000566687 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5961G>T at the cDNA level, p.Gln1987His (Q1987H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 6189G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln1987His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln1987His occurs at a position that is not conserved and is located in the BRC repeat region and RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Gln1987His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561617 SCV000661251 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000637728 SCV000759201 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 1987 of the BRCA2 protein (p.Gln1987His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. 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: 55935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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. 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.
Integrated Genetics/Laboratory Corporation of America RCV000779990 SCV000916972 uncertain significance not specified 2018-07-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5961G>T (p.Gln1987His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 120618 control chromosomes (ExAC). 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.5961G>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences RCV000049344 SCV000081776 probable-pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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