ClinVar Genomic variation as it relates to human health

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.994466

Variant summary: BRCA2 c.9118-2A>G 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: Four predict the variant abolishes a 3' acceptor site and creates a 3' acceptor site. Experimental evidence supports that this variant affects mRNA splicing (Machackova_2008, Acedo_2012). The variant allele was found at a frequency of 3.2e-05 in 250530 control chromosomes. c.9118-2A>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (ie Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22632462). ClinVar contains an entry for this variant (Variation ID: 52759). This variant is also known as 9346-2A>G. Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 9150152, 29339979, 29446198). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs81002862, gnomAD 0.04%). This sequence change affects an acceptor splice site in intron 23 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).

The c.9118-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 23 in the BRCA2 gene. This alteration has been reported in multiple familial breast/ovarian cancer cohorts, and has been described as a Finnish founder mutation (Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3; Sarantaus L et al. Int. J. Oncol. 2001 Apr;18:831-5; Huusko P et al. Am. J. Hum. Genet. 1998 Jun;62:1544-8; Sarantaus L et al. Eur. J. Hum. Genet. 2000 Oct;8:757-63; Vehmanen P et al. Am. J. Hum. Genet. 1997 May;60:1050-8; Kluska A et al. BMC Med Genomics. 2015 May;8:19). Minigene and RT-PCR functional studies have demonstrated exon skipping (Acedo A et al. Breast Cancer Res. 2012 May;14:R87) and production of an aberrant transcript lacking the first 7 base pairs of exon 24, resulting in a premature stop codon (Claes K et al. Genes Chromosomes Cancer. 2003 Jul;37:314-20), respectively. Of note, this alteration is also designated as 9346-2ntA>G and IVS23-2A>G in the published literature. 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.

This variant causes an A to G nucleotide substitution at the -2 position of intron 23 of the BRCA2 gene. Functional RNA studies have shown that this variant causes the activation of an out-of-frame cryptic acceptor site, resulting in a premature termination signal and truncated protein (PMID: 12759930, 18489799, 22632462). This variant has been reported in 17 female individuals affected with breast cancer, 8 male individuals affected with breast cancer, 2 individuals affected with ovarian cancer (PMID: 10995809, 11251181, 11504767, 12759930, 15548363, 15642173, 18489799) and has been identified in 21 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 0/53461 controls; p-value=0.033; Leiden Open Variation Database DB-ID BRCA2_000410 (PMID: 33471991). This variant is a known founder mutation in the Finnish European population and has been identified in 8/250530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Canonical splice site variant demonstrated to result in aberrant splicing leading to a null allele in a gene for which loss of function in a known mechanism of disease (PMID: 12759930, 22632462, 32398771); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9346-2A>G; This variant is associated with the following publications: (PMID: 22632462, 18489799, 9585608, 36467798, 36551643, 11251181, 30040829, 11504767, 23348723, 9150152, 20383589, 16211554, 25948282, 26843898, 11250694, 18821011, 11039575, 23893897, 25706666, 15024741, 23199084, 16141195, 26681312, 29446198, 24312913, 29339979, 28166811, 28726806, 30720243, 32853339, 31723001, 31131967, 31341520, 35469032, 31409081, 33461583, 33471991, 15548363, 10995809, 28918466, 30175445, 32398771, 12759930)