Submissions for variant NM_000059.4(BRCA2):c.4740_4741dup (p.Glu1581fs)

dbSNP: rs864622401

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241010	SCV000300780	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.
Invitae	RCV000206526	SCV000260489	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1581Valfs*37) 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: 20859677, 23469205). This variant is also known as 4969_4970insTG or 4968insGT. ClinVar contains an entry for this variant (Variation ID: 220160). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241010	SCV000327077	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413237	SCV000492468	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Baylor Genetics	RCV000476565	SCV000541002	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000483210	SCV000568468	pathogenic	not provided	2017-09-28	criteria provided, single submitter	clinical testing	This duplication of 2 nucleotides in BRCA2 is denoted c.4740_4741dupTG at the cDNA level and p.Glu1581ValfsX37 (E1581VfsX37) at the protein level. The normal sequence, with the bases that are duplicated in braces, is CATG[TG]AGAC. The duplication causes a frameshift which changes a Glutamic Acid to a Valine at codon 1581, and creates a premature stop codon at position 37 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. BRCA2 c.4740_4741dupTG, also known as 4970insTG, 4968insGT and 4970_4971insTG using alternate nomenclature, has been reported in association with breast cancer (Gallardo 2006, Carraro 2013). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483210	SCV000600604	pathogenic	not provided	2017-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003584567	SCV004362078	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4968insGT and 4970insTG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least six individuals and families affected with breast and/or ovarian cancer (PMID: 16261400, 20859677, 23469205, 28947987, 31125277). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000241010	SCV000591924	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Glu1581ValfsX37 duplication variant was identified in 3 of 760 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Carraro 2013, Gonzalez-Hormazabal 2011). The variant was also identified in the HGMD. The p.Glu1581ValfsX37 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1581 and leads to a premature stop codon 37 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic.