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

Total submissions: 10

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