Submissions for variant NM_000059.4(BRCA2):c.2312T>G (p.Leu771Ter)

gnomAD frequency: 0.00001  dbSNP: rs587782095

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241179	SCV000300506	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	RCV000130606	SCV000185481	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	The p.L771* pathogenic mutation (also known as c.2312T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2312. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration has been reported in two unrelated Austrian individuals with Hereditary Breast and Ovarian Cancer syndrome (Tea MK et al. Maturitas 2014 Jan; 77(1):68-72). 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	RCV000241179	SCV000326690	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657630	SCV000779373	pathogenic	not provided	2022-07-28	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; Observed in individuals with personal and/or family history consistent with pathogenic variants in this gene (Tea et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2540T>G; This variant is associated with the following publications: (PMID: 28152038, 27614696, 29446198, 30720243, 24156927)
Color Diagnostics, LLC DBA Color Health	RCV000130606	SCV000911670	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/31398 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496732	SCV001204081	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu771*) 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 present in population databases (rs587782095, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 24156927). ClinVar contains an entry for this variant (Variation ID: 141901). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000657630	SCV003814293	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496732	SCV000587628	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research