Submissions for variant NM_000059.4(BRCA2):c.125_132dup (p.Glu45fs)

dbSNP: rs483353112

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661431	SCV000783708	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.
GeneDx	RCV000478452	SCV000572388	pathogenic	not provided	2019-01-21	criteria provided, single submitter	clinical testing	This duplication of eight nucleotides in BRCA2 is denoted c.125_132dupATAATTCT at the cDNA level and p.Glu45IlefsX38 (E45IfsX38) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 353_360dupATAATTCT. The normal sequence, with the bases that are duplicated in brackets, is CCCT[dupATAATTCT]GAAC. The duplication causes a frameshift which changes a Glutamic Acid to an Isoleucine at codon 45, and creates a premature stop codon at position 38 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	RCV001193358	SCV001362120	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.125_132dupATAATTCT (p.Glu45IlefsX38) 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. The variant was absent in 251264 control chromosomes. To our knowledge, no occurrence of c.125_132dupATAATTCT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic while one of them also acknolwedges the lack of published evidence in affected individuals. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002413334	SCV002674658	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-03	criteria provided, single submitter	clinical testing	The c.125_132dupATAATTCT pathogenic mutation, located in coding exon 2 of the BRCA2 gene, results from a duplication of ATAATTCT at nucleotide position 125, causing a translational frameshift with a predicted alternate stop codon (p.E45Ifs*38). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193358	SCV003202741	pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 422823). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu45Ilefs*38) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478452	SCV004219502	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.