Submissions for variant NM_000059.4(BRCA2):c.4007_4008insCATC (p.Asp1337fs)

dbSNP: rs878853577

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000576604	SCV000784145	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.
Invitae	RCV000226629	SCV000283223	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1337Ilefs*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). This variant is not present in population databases (gnomAD no frequency). 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: 236860). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506343	SCV000600571	pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000576604	SCV000677823	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000226629	SCV000694729	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4007_4008insCATC (p.Asp1337IlefsX2) 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 230396 control chromosomes. To our knowledge, no occurrence of c.4007_4008insCATC in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000506343	SCV000778993	pathogenic	not provided	2019-05-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar but additional evidence is not available [SCV000784145.1; Landrum et al., 2016]
Color Diagnostics, LLC DBA Color Health	RCV000774946	SCV000909032	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 11 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.
Ambry Genetics	RCV000774946	SCV001183289	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	The c.4007_4008insCATC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from an insertion of 4 nucleotides at position 4007, causing a translational frameshift with a predicted alternate stop codon (p.D1337Ifs*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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000506343	SCV000591883	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Asp1337IlefsX2 insertion variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD databases. The p.Asp1337IlefsX2 insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1337 and leads to a premature stop codon at position 1338. 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 meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV000576604	SCV002588871	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing