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 2020-09-22 criteria provided, single submitter clinical testing The p.A2730P variant (also known as c.8188G>C), located in coding exon 17 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8188. The alanine at codon 2730 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in an individual affected with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). It was also identified in an individual with castration-resistant prostate cancer diagnosted at 57 whose tumor also had somatic loss of BRCA2 (VanderWeele DJ et al. Eur Urol Focus, 2018 Feb;). This alteration was found to be deleterious in a cell-based homology directed repair assay (Hart SN et al. Genet. Med., 2019 01;21:71-80). <span style="background-color:initial">Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, this alteration introduces a large physical change that will distort a local loop motif likely impacting DNA binding ability (Ambry internal data; Yang H et al. Science, 2002 Sep;297:1837-48; Crepin T et al. Structure, 2006 Oct;14:1511-25; Shahid T et al. Nat. Struct. Mol. Biol., 2014 Nov;21:962-8).<span style="background-color:initial"> In addition, the in silico prediction for this alteration is inconclusive. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Counsyl RCV000113886 SCV000488139 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Invitae RCV000456410 SCV000549726 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-24 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 RCV000586658 SCV000600789 likely pathogenic not provided 2019-04-12 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient in literature. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Color Health, Inc RCV000131217 SCV000906950 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-15 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 2730 in the DNA binding/OB tower domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a significantly reduced homology-directed repair activity of the BRCA2 protein (PMID: 29884841). This variant has been reported in an individual affected with high-risk breast cancer (PMID: 25186627) and in an individual affected with prostate cancer (PMID: 29398457). This variant has been identified in 2/31394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113886 SCV000147297 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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