Submissions for variant NM_000059.4(BRCA2):c.9117+1del

dbSNP: rs869320801

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Michigan Medical Genetics Laboratories, University of Michigan	RCV000210979	SCV000267828	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567065	SCV000661275	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The c.9117+1delG intronic variant, located in intron 22 of the BRCA2 gene, results from a deletion of one nucleotide within intron 22 of the BRCA2 gene. Another alteration impacting this splice donor site, c.9117+1G>A, is noted to be a Finnish founder mutation and has been reported in multiple breast and/or ovarian cancer families (Marroni F et al. Eur J Hum Genet. 2004 Nov;12(11):899-906; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72; Apostolou P et al. eLS. John Wiley & Sons, Ltd: Chichester. 2015 Jan). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Acedo A et al. Breast Cancer Res. 2012 May 25;14(3):R87). 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853398	SCV002242475	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 23 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and or ovarian cancer (PMID: 10449599, 15340362, 28724667, 29084914, 30702160). ClinVar contains an entry for this variant (Variation ID: 225757). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10449599, 22632462). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002478763	SCV002774271	likely pathogenic	not provided	2021-07-31	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001853398	SCV003923091	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9117+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248254 control chromosomes. To our knowledge, no occurrence of c.9117+1delG in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. In addition, other variants involving this splice site ( c.9117+1G>A, c.9117+1G>T) have been reported to associate with HBOC. Based on the evidence outlined above, the variant was classified as pathogenic.