Submissions for variant NM_000059.4(BRCA2):c.6980del (p.Ser2326_Leu2327insTer)

dbSNP: rs879255306

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)	RCV000238627	SCV000324502	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000238627	SCV000296554	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-25	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238627	SCV000327554	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482674	SCV000565694	pathogenic	not provided	2015-05-12	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted BRCA2 c.6980delT at the cDNA level and p.Leu2327Ter (L2327X) at the protein level. The normal sequence, with the base that is deleted in braces, is TCTT[T]AGAG. The deletion creates a nonsense variant, which changes a Leucine to a premature stop codon. Using alternate nomenclature, this variant would be defined as BRCA2 7208delT. Although this variant has not been previously reported to our knowledge, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, and is considered pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496430	SCV004847886	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Leu2327X variant in BRCA2 has not been previously reported in individuals with hereditary breast and/or ovarian cancer (HBOC) and was absent from large population studies, but has been reported in ClinVar (Variation ID: 252419). This nonsense variant leads to a premature termination codon at position 2327, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics	RCV004020974	SCV005029276	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The c.6980delT pathogenic mutation, located in coding exon 12 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6980, causing a translational frameshift with a predicted alternate stop codon (p.L2327*). This mutation has been reported in a patient at risk for hereditary breast cancer (Morgan JE et al. Hum Mutat, 2010 Apr;31:484-91) and in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 Dec;151:481-488). In addition to the clinical data presented in the literature, 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.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496430	SCV000587873	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research