Submissions for variant NM_007294.4(BRCA1):c.5467+1G>A

gnomAD frequency: 0.00001  dbSNP: rs80358145

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049003	SCV000077016	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 22 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with breast and ovarian cancer (PMID: 11428389, 19491284, 21913181, 25428789). This variant is also known as This variant is also known as IVS23+1G>A in the literature.. ClinVar contains an entry for this variant (Variation ID: 37673). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 22 and introduces a new termination codon (PMID: 11428389, 24667779). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 20104584, 21922593, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162888	SCV000213375	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	The c.5467+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 21 of the BRCA1 gene. This alteration was reported in a cohort of African American high risk breast cancer patients (Churpek JE, et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9) and has been classified as pathogenic by a personal and family history weighing algorithm (Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32). Another study reported this alteration in 1/478 high risk breast cancer patients (Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150). RNA assays have demonstrated that this alteration results in exon skipping of coding exon 21 (Ambry internal data; Laskie Ostrow K et al. Cancer Genet. Cytogenet. 2001 Jun;127:188-90; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM. et al. Nature 2018 10;562(7726):217-222). Of note, this alteration is also designated as IVS23 +1G>A in 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.
Counsyl	RCV000031254	SCV000220766	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-03	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031254	SCV000326319	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000430282	SCV000516012	pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in skipping of exon 22, resulting in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease (PMID: 11428389, 24667779); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 30209399); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5586+1G>A; This variant is associated with the following publications: (PMID: 21913181, 25724305, 11428389, 24667779, 26287763, 26852015, 25085752, 25428789, 28205045, 25863477, 26250392, 26187060, 29470806, 29310832, 30702160, 30720863, 29446198, 31174498, 30093976, 33151324, 25525159, 31825140, 32427313, 30787465, 34645131, 32164585, 36463295, 30209399)
Color Diagnostics, LLC DBA Color Health	RCV000162888	SCV000683319	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 22 of the BRCA1 gene. RNA studies have shown that this variant causes the out-of-frame skipping of exon 21, resulting in a premature truncation in carrier RNA and minigene splicing assay (PMID: 11428389, 25428789). A functional study reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer and 2 unaffected individuals (PMID: 11428389, 18159056, 19491284, 21913181, 25428789, 25863477, 28205045, 30093976, 30287823, 33471991, 34657357, 35671604; Color internal data) and pancreatic cancer (PMID: 36463295). An analysis of the health history of 54 carriers reported that this variant has a pathogenic impact (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430282	SCV000888948	pathogenic	not provided	2016-05-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049003	SCV000916825	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5467+1G>A 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 canonical 5' splicing donor site, and two predict the variant creates/strengthens an existing cryptic 5' splice donor site 5nt into intron 22. Experimental evidence has confirmed that this variant affects mRNA splicing, resulting in the skipping of exon 23 (Laskie_2001, Steffensen_2014). At least one publication reports experimental evidence evaluating an impact on protein function (Findlay_2018) and the variant effect resulted in <10% of normal activity. The variant allele was found at a frequency of 6.6e-06 in 150970 control chromosomes (gnomAD v3.1.2). c.5467+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Laskie_2001, Litton_2012, Judkins_2005, John_2007, Haffty_2009, Kang_2015, Mannan_2016, Chan_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000031254	SCV004215043	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031254	SCV000053858	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-01-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031254	SCV000145521	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031254	SCV001243929	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000031254	SCV004243911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing