ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8188G>C (p.Ala2730Pro) (rs80359066)

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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 RCV000131217 SCV000186169 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113886 SCV000147297 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131217 SCV000906950 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
Counsyl RCV000113886 SCV000488139 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000586658 SCV000210467 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8188G>C at the cDNA level, p.Ala2730Pro (A2730P) at the protein level, and results in the change of an Alanine to a Proline (GCC>CCC). This variant, also known BRCA2 8416G>C using alternate nomenclature, has not, to our knowledge, been published as pathogenic or benign. BRCA2 Ala2730Pro was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Alanine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ala2730Pro occurs at a position where amino acids with properties similar to Alanine are tolerated across species and is located within the DSS1 contacting residue of the DNA binding domain and within the region of interaction with SHFM1 (Marston 1999, Yang 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ala2730Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586658 SCV000695134 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 variant, c.8188G>C (p.Ala2730Pro) located in the Nucleic Acid-Binding, OB-Fold domain (via InterPro) causes an alteration of a conserved nucleotide, which 5/5 in silico programs predicting a "deleterious" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121398, which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, although a publication, Karchin_2008, assessed the variant using a computational method and was predicted to be "likely deleterious." The variant of interest has been classified by multiple reputable clinical laboratories with conflicting classifications "likely pathogenic" or "uncertain significance," without providing information for an independent assessment. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000456410 SCV000549726 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2730 of the BRCA2 protein (p.Ala2730Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 126168). Experimental studies have shown that this missense change reduces homology-directed repair (HDR) activity of the BRCA2 protein (PMID: 29884841). 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 RCV000160150 SCV000600789 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing

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