ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6713A>G (p.Asp2238Gly) (rs80358895)

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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 RCV000130198 SCV000185035 likely benign Hereditary cancer-predisposing syndrome 2017-06-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000656798 SCV000210401 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6713A>G at the cDNA level, p.Asp2238Gly (D2238G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 6941A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp2238Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp2238Gly 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 Asp2238Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212251 SCV000600715 uncertain significance not specified 2017-03-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130198 SCV000903526 likely benign Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001110667 SCV001268130 uncertain significance Fanconi anemia, complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000113631 SCV001268131 uncertain significance Breast-ovarian cancer, familial 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001351104 SCV001545543 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 2238 of the BRCA2 protein (p.Asp2238Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52166). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The glycine 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113631 SCV000146914 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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