Submissions for variant NM_000059.4(BRCA2):c.6865_6866del (p.Leu2289fs)

dbSNP: rs2137536911

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797948	SCV002041815	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6865_6866delTT (p.Leu2289IlefsX3) results in a premature termination codon in exon 12, 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 246146 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6865_6866delTT in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. A transcript lacking exon 12 (resulting in an in-frame deletion change in the encoded protein) has been determined to occur naturally (PMID: 27060066). A recent study examining the effect of 11 truncation variants located within exon 12, determined that 2 of them had a significant spliceogenic effect leading to major exon 12 skipping (PMID 32046981). These two nonsense variants were determined to have a mild functional effect and along with segregation analysis data from families carrying these variants, lead the authors to conclude that the hypomorphic activity observed for these variants might confer moderate or low risks of breast cancer. Nevertheless, the remaining 9 truncation variants were not determined to have significant spliceogenic effect and will therefore be expected to lead to truncation or absence of the encoded protein. Based on the evidence outlined above, and taking into consideration the special conditions that may exist for variants located in exon 12 of BRCA2, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001797948	SCV003325008	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2289Ilefs*3) 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: 1329057). For these reasons, this variant has been classified as Pathogenic.