Submissions for variant NM_000059.4(BRCA2):c.5281G>T (p.Gly1761Ter)

dbSNP: rs886038122

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241157	SCV000300855	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241157	SCV000327192	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000241157	SCV000743305	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637612	SCV000759078	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1761*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 254556). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000772133	SCV000905233	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 28724667). 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). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV000772133	SCV002645228	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-01	criteria provided, single submitter	clinical testing	The p.G1761* pathogenic mutation (also known as c.5281G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5281. This changes the amino acid from a glycine to a stop codon within coding exon 10. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV004804969	SCV005424476	pathogenic	BRCA2-related cancer predisposition	2024-08-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individual affected with breast and ovarian cancer (PMID: 28724667, 30982232, 31742824) and in 1 family among 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). Based on the available evidence, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000241157	SCV000733264	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723829	SCV001953300	pathogenic	not provided		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000241157	SCV004022176	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-21	no assertion criteria provided	research	The variant NM_000059.4:c.5281G>T (chr13:32339636) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.