Submissions for variant NM_000059.4(BRCA2):c.1456C>T (p.Gln486Ter)

dbSNP: rs80358434

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112924	SCV000300432	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.
Ambry Genetics	RCV000219957	SCV000275360	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The p.Q486* pathogenic mutation (also known as c.1456C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1456. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been identified in a family with hereditary breast and/or ovarian cancer from Norway (Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112924	SCV000326557	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112924	SCV000605658	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000520967	SCV000620196	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1684C>T; This variant is associated with the following publications: (PMID: 21523855, 20167696, 29339979, 29446198, 20104584, 32377563, 31853058, 32918181)
Counsyl	RCV000112924	SCV000677669	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496375	SCV000694539	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1456C>T (p.Gln486X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 243790 control chromosomes. c.1456C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, a consotrium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=5)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496375	SCV001586040	pathogenic	Hereditary breast ovarian cancer syndrome	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln486*) 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 hereditary breast and ovarian cancer (PMID: 29339979, 29446198). ClinVar contains an entry for this variant (Variation ID: 51128). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000520967	SCV002047812	pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing	The BRCA2 c.1456C>T; p.Gln486Ter variant (rs80358434) is reported in the literature in several individuals affected with hereditary breast and/or ovarian cancer (Heramb 2018, Mattocks 2010, Rebbeck 2018). This variant is also reported in ClinVar (Variation ID: 51128), and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Mattocks CJ et al. Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning. Clin Chem. 2010 Apr;56(4):593-602. PMID: 20167696. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198.
Revvity Omics, Revvity	RCV000520967	SCV003812419	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473305	SCV004210465	pathogenic	Familial cancer of breast	2022-10-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520967	SCV005624322	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	The BRCA2 c.1456C>T (p.Gln486*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 29339979 (2018), 29446198 (2018)). 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)	RCV000112924	SCV000145874	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-06-22	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496375	SCV000587598	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research