Submissions for variant NM_000059.4(BRCA2):c.3336del (p.Glu1113fs)

dbSNP: rs398122763

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)	RCV000077706	SCV000300621	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077706	SCV000267757	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077706	SCV000296662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000077706	SCV000489566	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001232803	SCV001405372	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1113Asnfs*6) 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 clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91798). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003343632	SCV004052503	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The c.3336delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 3336, causing a translational frameshift with a predicted alternate stop codon (p.E1113Nfs*6). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001232803	SCV004122588	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3336delA (p.Glu1113AsnfsX6) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 238638 control chromosomes. To our knowledge, no occurrence of c.3336delA in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077706	SCV000109509	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-06-11	no assertion criteria provided	clinical testing