Submissions for variant NM_000059.4(BRCA2):c.2253_2254del (p.Asp752fs)

dbSNP: rs398122744

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)	RCV000077681	SCV000300501	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.
GeneDx	RCV000481582	SCV000569421	pathogenic	not provided	2016-10-07	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in BRCA2 is denoted c.2253_2254delTG at the cDNA level and p.Asp752LeufsX10 (D752LfsX10) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATAC[TG]ACTT. Using alternate nomenclature, this variant would be defined as BRCA2 2481delTG. The deletion causes a frameshift which changes an Aspartic Acid to a Leucine at codon 752, and creates a premature stop codon at position 10 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	RCV000781073	SCV000918882	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2253_2254delTG (p.Asp752LeufsX10) 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.2287delC, p.His763fsX9; c.2330dupA, p.Asp777fsX11; c.2368G>T, p.Glu790X). The variant was absent in 277038 control chromosomes. To our knowledge, no occurrence of c.2253_2254delTG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781073	SCV002233072	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp752Leufs*10) 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 has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 91773). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460734	SCV004216067	likely pathogenic	Familial cancer of breast	2023-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004601105	SCV005102052	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The c.2253_2254delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 2253 to 2254, causing a translational frameshift with a predicted alternate stop codon (p.D752Lfs*10). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077681	SCV000109484	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-09-23	no assertion criteria provided	clinical testing