ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6714T>G (p.Asp2238Glu) (rs28897742)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212252 SCV000210402 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6714T>G at the cDNA level, p.Asp2238Glu (D2238E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). Using alternate nomenclature, this variant would be defined as BRCA2 6942T>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Asp2238Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asp2238Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218646 SCV000272984 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-04 criteria provided, single submitter clinical testing The p.D2238E variant (also known as c.6714T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6714. The aspartic acid at codon 2238 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000218646 SCV000908549 likely benign Hereditary cancer-predisposing syndrome 2015-10-14 criteria provided, single submitter clinical testing
Invitae RCV001351921 SCV001546436 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 2238 of the BRCA2 protein (p.Asp2238Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs28897742, ExAC 0.003%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52167). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113632 SCV000146915 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356936 SCV001552236 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Asp2238Glu was not identified in the literature nor was it identified in HGMD, LOVD, or COSMIC. It was identified in the UMD one time and BIC two times, both with unknown significance, and the Clinvar database (1x from Invitae, classification not provided and 1x from BIC, as uncertain significance). It is listed in the dbSNP database (rs28897742) “With Uncertain significance allele”, but frequency information was not available from the general population (ESP project, 1000 genomes, HapMap). The p.Asp2238 variant is not well conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. However, this information is not very predictive of pathogenicity. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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