Submissions for variant NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)

dbSNP: rs80359251

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV000112825	SCV004101448	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-12	reviewed by expert panel	curation	The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112825	SCV000328177	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000112825	SCV000677709	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000657637	SCV000779381	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 110 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 10153G>T; This variant is associated with the following publications: (PMID: 22678057, 26332594, 29988080, 29446198, 18607349, 32914019, 10733923)
Color Diagnostics, LLC DBA Color Health	RCV001184568	SCV001350586	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 27 of the BRCA2 gene, creating a premature translation stop signal in the last coding exon. Functional studies in mouse embryonic stem cells have provided conflicting conclusions on variant impact on the protein function (PMID 18607349, 29988080). Although both studies indicated increased sensitivity to DNA damaging agents, the mutant protein was able to complement BRCA2-deficiency and showed only partially reduced homology-directed recombination activity. This variant has been reported in an individual affected with ovarian cancer (PMID: 18607349) and has been identified in 1 family among the CIMBA participants (PMID: 29446198).. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000496671	SCV001511659	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu3309*) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the BRCA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or endometrial cancer (PMID: 29446198, 32914019). ClinVar contains an entry for this variant (Variation ID: 52919). 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.
Ambry Genetics	RCV001184568	SCV002691029	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.E3309* variant (also known as c.9925G>T), located in coding exon 26 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9925. This changes the amino acid from a glutamic acid to a stop codon within coding exon 26. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRCA2 and is not expected to trigger nonsense-mediated mRNA decay. Functional studies have found conflicting evidence for this variant, with this variant being shown to cause hypersensitivity to DNA damaging agents (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81), but also demonstrated to maintain a high rate of homology directed repair efficiency (Mesman RLS et al. Genet. Med., 2019 02;21:293-302). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496671	SCV002766459	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9925G>T (p.Glu3309X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is creates a stop codon one amino acid downstream of the common pathogenic variant p.Tyr3308X. The variant was absent in 251252 control chromosomes. c.9925G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Kuznetsov_2008, Smith_2019). These data indicate that the variant may be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (Kuznetsov_2008, Biswas_2012, Mesman_2018). The most pronounced variant effect results in a 25% reduction in HDR activity as well as increased sensitivity to DNA-damaging agents (Mesman_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant with conflicting assessments as pathogenic (n = 2), likely pathogenic (n = 2), and unknown significance (n = 2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112825	SCV000145733	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-04-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496671	SCV000588017	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735634	SCV000863772	likely pathogenic	Breast and/or ovarian cancer	2003-10-03	no assertion criteria provided	clinical testing