Submissions for variant NM_000059.4(BRCA2):c.67+1G>C

dbSNP: rs81002796

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240786	SCV000265920	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000217482	SCV000274286	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-25	criteria provided, single submitter	clinical testing	The c.67+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 1 of the BRCA2 gene. This alteration has been detected in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS ONE 2016 Jun;11:e0156789). Additionally, two other disease-causing mutations at the same position, c.67+1G>A and c.67+1G>T, have been identified in families with HBOC (Meyer P et al. Hum. Mutat. 2003 Sep;22:259; Sagi M et al. Fam. Cancer. 2011 Mar;10(1):59-63) and functional studies have shown that both of these alterations result in skipping of exon 2 (Bonatti F et al. Cancer Genet Cytogenet. 2006 Oct 15;170(2):93-101; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. As such, this alteration is classified as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000239221	SCV000296565	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818507	SCV002070167	pathogenic	not provided	2020-03-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853355	SCV002228271	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-23	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 disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17011979). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 27257965, 30702160, 21063910). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224450). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).
Genetics and Molecular Pathology, SA Pathology	RCV000239221	SCV002761856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-11-09	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005237729	SCV005882940	pathogenic	Inherited breast cancer and ovarian cancer	2024-10-16	criteria provided, single submitter	clinical testing	PVS1,PS4_Supporting,PM2_Supporting