ClinVar Miner

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

dbSNP: rs80359100
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Total submissions: 14
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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, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000510027 SCV000607759 likely pathogenic Hereditary cancer-predisposing syndrome 2024-11-20 criteria provided, single submitter clinical testing The c.8486A>G variant (also known as p.Q2829R) is located in coding exon 18 of the BRCA2 gene. This results from an A to G substitution at nucleotide position 8486 which is the second to last nucleotide of the exon. The glutamine at codon 2829 is replaced by arginine, an amino acid with highly similar properties. This alteration has been identified in multiple breast cancer cohorts, including male breast cancer (Scott CL et al. Hum Genet, 2003 May;112:542-51; Deb S et al. BMC Cancer, 2012 Nov;12:510; Kim JH et al. Sci Rep, 2021 04;11:8485). 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; Machackova E et al. Klin Onkol. 2019;32:51-71; Wai HA et al. Genet Med, 2020 06;22:1005-1014; Biswas K et al. NPJ Genom Med, 2020 Dec;5:52). Of note, this alteration is also referred to as 8714A>G in the published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. 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 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 2023-05-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284445 SCV001470248 pathogenic not provided 2024-05-14 criteria provided, single submitter clinical testing The BRCA2 c.8486A>G (p.Gln2829Arg) variant has been reported in the published literature in individuals and families with breast and/or ovarian cancer (PMIDs: 33875706 (2021), 29446198 (2018), 27616075 (2016), 22762150 (2012), 12601471 (2003)). Experimental studies show the variant is damaging to protein function by reducing cell survival (PMID: 33293522 (2020)) and causing improper splicing of exon 19 (PMIDs: 34663891 (2021), 32123317 (2020), 27060066 (2016), 22505045 (2012), 16489001 (2006)). A multifactorial likelihood analysis reports a posterior probability suggestive of the variant being pathogenic (PMID: 31131967 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000590582 SCV001511657 pathogenic Hereditary breast ovarian cancer syndrome 2024-05-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2829 of the BRCA2 protein (p.Gln2829Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with several individuals with a personal or family history of breast cancer and a personal or family history of breast cancer (PMID: 22505045, 22762150, 27616075, 29446198, 30415210). ClinVar contains an entry for this variant (Variation ID: 38161). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (PMID: 16489001, 22505045, 27616075). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Gly2793Arg) have been determined to be pathogenic (PMID: 12442275, 15889636, 16030099, 23108138, 23233716, 25777348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV000031744 SCV002761851 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2021-04-20 criteria provided, single submitter clinical testing The BRCA2:c.8486A>G variant is classified as PATHOGENIC (PVS1_O_Strong, PM2, PP3, PP1_Strong). BRCA2:c.8486A>G is a single nucleotide substitution in exon 19 that predicts a missense change from Glutamine to Arginine at position 2829; NP_000050.2(BRCA2).p.(Gln2829Arg). This variant resides at the penultimate coding nucleotide upstream of the adjacent splice donor boundary. No alternative wildtype splice isoforms exist for this gene. BRCA2:c.8486A>G (rs80359100) is not recorded in gnomAD nor the control database FLOSSIES (PM2). Computational analysis supports a deleterious effect, predicting loss of normal wildtype splicing at the adjacent intron19 splice donor site (Alamut Visual Plus 1.5.1) (PP3). Independent splicing assays confirm this variant disrupts normal mRNA splicing, causing in-frame skipping of exon 19 resulting in a transcript that encodes loss of 51 amino acids from the highly conserved DNA binding domain important to normal BRCA2 function (Houdayer et al., 2012 PMID:22505045, Acedo et al., 2015 PMID:25382762, Kraus et., 2017 PMID:27616075, Wai et al., 2020 PMID:32123317) (PVS1_O_Strong). Another BRCA2 splicing variant (BRCA2:c.8487+1G>A) downstream of BRCA2:c.8486A>G also causes in-frame skipping of exon 19 and has been classified as pathogenic by the ENIGMA Expert Panel (ClinVar Variation ID: 52602). BRCA2:c.8486A>G has been reported in the scientific literature in multiple unrelated individuals with breast cancer (Kraus et al., 2017 PMID:27616075, Lee et al., 2018 PMID:30415210). This variant demonstrates disease segregation in 2 unrelated families with BRCA2-related cancers (South Australian Clinical Genetics Service; personal communication) (PP1_Strong). Multiple diagnostic laboratories report this variant as Pathogenic/Likely Pathogenic in patients with hereditary breast and ovarian cancer syndrome (ClinVar Variation ID: 38161). This variant is listed in HGMD as ‘disease causing mutation?’ in association with Breast cancer (Accession: CM128970).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001284445 SCV004026425 likely pathogenic not provided 2023-06-12 criteria provided, single submitter clinical testing PM4, PM2_SUP, PS3, BP4
Color Diagnostics, LLC DBA Color Health RCV000510027 SCV004362752 likely pathogenic Hereditary cancer-predisposing syndrome 2024-01-31 criteria provided, single submitter clinical testing This variant changes the penultimate nucleotide c.A of exon 19 of the BRCA2 gene and is predicted to impair RNA splicing at the intron 19 splice donor site. This variant is also known as 8714A>G in the literature. RNA studies using carrier-derived lymphocytes have shown that this variant causes in-frame skipping of exon 19 (PMID: 22505045, 29750258, 32123317). A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in individuals affected with breast or ovarian cancer, including a male individual (PMID: 23146383, 27616075, 33875706). This variant has been observed in at least 4 suspected hereditary breast and ovarian cancer families (PMID: 16489001, 20815029, 26014432, 29446198, 31409081). A multifactorial analysis reported this variant to have a segregation likelihood ratio for pathogenicity of 14.295, derived from 3 families (PMID: 31131967). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health RCV004803080 SCV005425800 likely pathogenic BRCA2-related cancer predisposition 2024-03-25 criteria provided, single submitter clinical testing This variant changes the penultimate nucleotide c.A of exon 19 of the BRCA2 gene and is predicted to impair RNA splicing at the intron 19 splice donor site. This variant is also known as 8714A>G in the literature. RNA studies using carrier-derived lymphocytes have shown that this variant causes in-frame skipping of exon 19 (PMID: 22505045, 29750258, 32123317). A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in individuals affected with breast or ovarian cancer, including a male individual (PMID: 23146383, 27616075, 33875706). This variant has been observed in at least 4 suspected hereditary breast and ovarian cancer families (PMID: 16489001, 20815029, 26014432, 29446198, 31409081). A multifactorial analysis reported this variant to have a segregation likelihood ratio for pathogenicity of 14.295, derived from 3 families (PMID: 31131967). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV004803080 SCV005917642 likely pathogenic BRCA2-related cancer predisposition 2020-06-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031744 SCV000054351 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 flagged submission clinical testing
Institute of Human Genetics, Medical University Innsbruck RCV000031744 SCV000212031 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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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