ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5927G>T (p.Gly1976Val) (rs587782751)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132261 SCV000187344 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting benign classification
Color RCV000132261 SCV000906120 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Counsyl RCV000663212 SCV000786398 uncertain significance Breast-ovarian cancer, familial 2 2018-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000586206 SCV000321472 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5927G>T at the cDNA level, p.Gly1976Val (G1976V) at the protein level, and results in the change of a Glycine to a Valine (GGG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 6155G>T. This variant has been observed in at least one individual with early-onset breast cancer and one individual with ovarian cancer (Lee 2008, Alsop 2012). BRCA2 Gly1976Val was not observed at a significant frequency in large population cohorts (Lek 2016). BRCA2 Gly1976Val is located within the BRC7 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Gly1976Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000203955 SCV000494415 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-06-06 criteria provided, single submitter clinical testing Variant summary: This variant involves alteration of a conserved nucleotide located in BRC repeat7 domain and 4/4 in silico tools predict a deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.002% (2/9952 chromosomes), exclusively in individuals of African descent. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). This variant has been found in individuals with Br/OvC without evidence for causality. The variant is classified as VUS by other clinical laboratories and databases. Due to limited clinical data and the lack of functional studies, the variant was classified as a variant of uncertain significance until additional information becomes available.
Integrated Genetics/Laboratory Corporation of America RCV000586206 SCV000694919 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing Variant summary: This variant involves alteration of a conserved nucleotide located in BRC repeat7 domain and 4/4 in silico tools predict a deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.002% (2/9952 chromosomes), exclusively in individuals of African descent. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). This variant has been found in individuals with Br/OvC without evidence for causality. The variant is classified as VUS by other clinical laboratories and databases. Due to limited clinical data and the lack of functional studies, the variant was classified as a variant of uncertain significance until additional information becomes available.
Invitae RCV000203955 SCV000259454 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1976 of the BRCA2 protein (p.Gly1976Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs587782751, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 18284688, 22711857, 26287763). This variant is also known as 6155G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 142829). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254817 SCV000600668 uncertain significance not specified 2017-03-25 criteria provided, single submitter clinical testing

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