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

dbSNP: rs80359100

Total submissions: 14

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