Submissions for variant NM_000059.4(BRCA2):c.4037del (p.Thr1346fs)

gnomAD frequency: 0.00001  dbSNP: rs1162394508

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)	RCV000661772	SCV000784086	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508205	SCV000600573	likely pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533922	SCV000635329	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1346Metfs*28) 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 present in population databases (no rsID available, gnomAD 0.007%). 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: 438976). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000533922	SCV001338211	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4037delC (p.Thr1346MetfsX28) 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 237372 control chromosomes. c.4037delC has been reported in individuals affected with Hereditary Breast and Ovarian Cancer in the ClinVar database although to our knowledge no published reports of its occurrence in patients with HBOC have been ascertained. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One expert panel and two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000533922	SCV004014995	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000533922	SCV004848025	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The p.Thr1346fs variant in BRCA2 has not been previously reported in individuals with BRCA2-associated cancers or in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 28 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein.