Submissions for variant NM_000059.4(BRCA2):c.8208_8209insAG (p.Leu2737fs)

dbSNP: rs483353122

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)	RCV000113888	SCV000301254	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113888	SCV000327839	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496939	SCV001207565	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2737Serfs*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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 31273614). This variant is also known as c.8437insAG. ClinVar contains an entry for this variant (Variation ID: 126169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004019602	SCV005030594	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The c.8208_8209insAG pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from an insertion of two nucleotides at position 8208, causing a translational frameshift with a predicted alternate stop codon (p.L2737Sfs*2). This alteration was identified in an individual diagnosed with breast cancer (Gervas P et al. Mol Biol Rep, 2019 Oct;46:5537-5541). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113888	SCV000147299	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496939	SCV000587938	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research