Submissions for variant NM_000059.4(BRCA2):c.1733del (p.Gly578fs)

dbSNP: rs879255326

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)	RCV000661865	SCV000784191	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneKor MSA	RCV000239261	SCV000296814	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes one base from exon 10 of the BRCA2 mRNA (c.1733delG), It results in a frame-shift creating a new stop codon at amino acid residue 578, thus resulting in a truncated protein. Truncating variants in the BRCA2 gene are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID:252442).
Ambry Genetics	RCV000509861	SCV000607881	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The c.1733delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1733, causing a translational frameshift with a predicted alternate stop codon (p.G578Vfs*2). 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.
GeneDx	RCV000657341	SCV000779073	pathogenic	not provided	2018-02-23	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA2 is denoted c.1733delG at the cDNA level and p.Gly578ValfsX2 (G578VfsX2) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 1961delG. The normal sequence, with the base that is deleted in brackets, is GCAG[delG]TTTA. The deletion causes a frameshift which changes a Glycine to a Valine at codon 578, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781160	SCV000919034	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-12-10	criteria provided, single submitter	clinical testing	Variant summary: The variant, BRCA2 c.1733delG (p.Gly578ValfsX2) 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 (eg. c.1736T>G (p.Leu579X), c.1796_1800delCTTAT (p.Ser599X), c.2254_2257delGACT (p.Asp752fsX19)). The variant was absent in 245778 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1733delG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657341	SCV001133691	pathogenic	not provided	2019-01-30	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. To the best of our knowledge, this variant has not been reported in the published literature. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000509861	SCV001346075	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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. To our knowledge, 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.
Invitae	RCV000781160	SCV002189357	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly578Valfs*2) 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). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 252442).