ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8486A>G (p.Gln2829Arg) (rs80359100)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031744 SCV000327902 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000510027 SCV000607759 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing The p.Q2829R variant (also known as c.8486A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8486. The glutamine at codon 2829 is replaced by arginine, an amino acid with highly similar properties. Multiple RNA studies have shown that this alteration, as well as a close match alteration BRCA2 c.8486A>T, leads to skipping of coding exon 18 (Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102; Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). This amino acid and nucleotide position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by protein in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590582 SCV000695156 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8486A>G (p.Gln2829Arg) variant involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome for this variant. This variant is located at < 2nt from the intron-exon junction, which 3/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicting that this variant may affect ESE binding sites for SRp50 and SF2/ASF and might add binding sites for SRp55. One functional study, Houdayer _2012, testing this variant in lymphocytes found it to cause an inframe mutation resulting in exon 19 skipping, with no wildtype transcript being produced. This variant is absent in 120974 control chromosomes, which does not exceed the estimated maximum expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant was observed in affected individuals via publications. Multiple clinical diagnostic laboratories/reputable databases have reported the variant with conflicting classifications, predominantly as "likely pathogenic/pathogenic," and others classifying it as "uncertain significance." Taken together, this variant is classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170976 SCV001333636 likely pathogenic Breast and/or ovarian cancer 2017-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284445 SCV001470248 uncertain significance not provided 2020-03-18 criteria provided, single submitter clinical testing
Invitae RCV000590582 SCV001511657 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-04-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2829 of the BRCA2 protein (p.Gln2829Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with a personal or family history of breast cancer (PMID: 22762150, 30415210, 27616075, 22505045, 29446198). ClinVar contains an entry for this variant (Variation ID: 38161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27616075, 22505045, 25382762). 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.
Research and Development, ARUP Laboratories RCV001642479 SCV001852797 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031744 SCV000054351 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031744 SCV000212031 likely pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
CZECANCA consortium RCV001170976 SCV001451886 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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