Submissions for variant NM_000059.4(BRCA2):c.5279C>G (p.Ser1760Ter)

dbSNP: rs80358751

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113414	SCV000282403	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044625	SCV000072638	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1760*) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21895635). This variant is also known as 5507C>G. ClinVar contains an entry for this variant (Variation ID: 51833). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131074	SCV000186004	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The p.S1760* pathogenic mutation (also known as c.5279C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5279. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation (designated as 5507C>G) was identified in a Costa Rican female diagnosed with breast cancer at age 51, who also had a family history of breast cancer (Gutierrez Espeleta GA. et al. Clin Genet. 2012 Nov;82(5):484-8). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113414	SCV000327191	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113414	SCV000488204	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131074	SCV000683691	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-12	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 21895635, 34218100, DOI: https://doi.org/10.1182/blood.V114.22.1102.1102) and ovarian cancer (PMID: 30441849). This variant has been identified in 10 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study this variant was reported in 1/60466 cases and 0/53461 controls (p-value=1), (PMID: 33471991). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044625	SCV001362830	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5279C>G (p.Ser1760X) 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. The variant was absent in 245312 control chromosomes (gnomAD). c.5279C>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000131074	SCV002536121	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	curation
Baylor Genetics	RCV003460591	SCV004214561	pathogenic	Familial cancer of breast	2021-07-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476928	SCV004219682	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	The BRCA2 c.5279C>G (p.Ser1760*) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 21895635 (2012), 28888541 (2017), and 34218100 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113414	SCV000146587	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2001-02-16	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044625	SCV000587757	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research