Submissions for variant NM_000059.4(BRCA2):c.2731del (p.Glu911fs)

dbSNP: rs80359344

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113084	SCV000300553	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	RCV000562830	SCV000673112	pathogenic	Hereditary cancer-predisposing syndrome	2016-11-14	criteria provided, single submitter	clinical testing	The c.2731delG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 2731, causing a translational frameshift with a predicted alternate stop codon. This mutation (designated as 2959delG) has been reported in one family with Hereditary Breast and Ovarian Cancer (Lubinski J et al. Fam. Cancer 2004;3:1-10). 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.
Color Diagnostics, LLC DBA Color Health	RCV000562830	SCV000683498	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-02	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one hereditary breast and ovarian cancer (HBOC) family (PMID 15131399). 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	RCV000496863	SCV000694622	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2731delG (p.Glu911Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.2808delA/p.K936fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120768 control chromosomes and has been reported in at-least one out of 440 families with known BRCA2 mutations. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic until additional reports of its presence among unrelated probands with HBOC and supporting experimental data are obtained.
Invitae	RCV000496863	SCV001585161	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (HBOC) syndrome (PMID: 15131399). This variant is also known as 2959delG in the literature. ClinVar contains an entry for this variant (Variation ID: 51332). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu911Lysfs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113084	SCV000146099	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1998-03-04	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496863	SCV000587640	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research