Submissions for variant NM_000059.4(BRCA2):c.67+2T>G

dbSNP: rs81002885

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000496567	SCV001204937	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 17011978, 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 431285). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 21063910). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV001591133	SCV001824576	likely pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; Also known as 295+2T>G
Ambry Genetics	RCV002367672	SCV002664900	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	clinical testing	The c.67+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 1 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496567	SCV000587533	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research