Submissions for variant NM_000059.4(BRCA2):c.5065_5066delinsAAA (p.Ala1689fs)

dbSNP: rs276174852

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)	RCV000113372	SCV000300822	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.
Color Diagnostics, LLC DBA Color Health	RCV000584719	SCV000688915	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides and inserts 3 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
GeneDx	RCV000657228	SCV000778954	pathogenic	not provided	2017-06-14	criteria provided, single submitter	clinical testing	This combined deletion and insertion is denoted BRCA2 c.5065_5066delGCinsAAA at the cDNA level and p.Ala1689LysfsX6 (A1689KfsX6) at the protein level. The surrounding sequence is TGAA[delGC][insAAA]AAAAAAAT. The variant causes a frameshift which changes an Alanine to a Lysine at codon 1689, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also published as BRCA2 5293delGCinsAAA using alternate nomenclature, this variant has been reported in at least one family with breast and/or ovarian cancer (Lubinski 2004). We consider BRCA2 c.5065_5066delGCinsAAA to be pathogenic.
Invitae	RCV000496795	SCV000831497	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1689Serfs*6) 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 personal and/or family history of BRCA2-related cancers (PMID: 15131399). This variant is also known as 5293delGCinsAAA . For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000584719	SCV001185381	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-21	criteria provided, single submitter	clinical testing	The c.5065_5066delGCinsAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from the deletion of two nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.A1689Kfs*6). This pathogenic mutation has been reported in one HBOC family (Lubinski J et al. Fam. Cancer. 2004;3:1-10). Of note, this mutation is also referred to as 5293delGCinsAAA in some literature. 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113372	SCV000146527	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496795	SCV000587740	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research