Submissions for variant NM_007294.4(BRCA1):c.5278-1G>C

gnomAD frequency: 0.00001  dbSNP: rs80358099

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129416	SCV000184186	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The c.5278-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 19 of the BRCA1 gene. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families (De la Hoya M et al. Int J Cancer. 2002 Feb 1;97(4):466-71; Rashid MU et al. BMC Cancer. 2016 Aug 23;16(1):673; Pelttari LM et al. Clin Genet. 2017 Aug 12; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Fang M et al. Oncol Lett, 2018 Mar;15:3068-3074; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Li JY et al. Int J Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Deng M et al. Int J Cancer, 2019 09;145:1517-1528). RNA analyses demonstrated skipping of coding exon 19 (also known as exon 21) as a result of this alteration (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another 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;562:217-222). Of note, this alteration is also designated as IVS20-1G>C in published literature. 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor 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. As such, this alteration is classified as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077612	SCV000326243	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482206	SCV000566733	pathogenic	not provided	2021-09-20	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in abnormal splicing leading to a null allele in a gene for which loss-of-function is a known mechanism of disease (Houdayer 2012); Observed in individuals with BRCA1-related cancer (de la Hoya 2002, Rashid 2016, Pelttari 2017, Fang 2018, Li 2019); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 5397-1G>C and IVS20-1G>C; This variant is associated with the following publications: (PMID: 11802208, 31131967, 22505045, 30209399, 29435039, 27553291, 29752822, 28802053, 12955716, 26681312, 30702160, 30720863, 30078507, 29446198, 25525159)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482206	SCV001133621	pathogenic	not provided	2019-06-28	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Color Diagnostics, LLC DBA Color Health	RCV000129416	SCV001353827	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 19 of the BRCA1 gene. A study using peripheral blood-derived RNA from a carrier has shown that this variant causes skipping of exon 20 (also known as exon 21 in the literature) and is expected to result in an absent or non-functional protein product (PMID: 22505045). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 12955716, 28802053, 29435039, 29752822, 30078507, 30287823, 30720863, 31528241, 35377489; Color internal data). 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.
Invitae	RCV000496568	SCV001585651	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-02	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 11802208, 12955716, 16998791, 27553291, 28802053, 29176636). ClinVar contains an entry for this variant (Variation ID: 55501). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 19 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496568	SCV003801058	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5278-1G>C 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. Three predict the variant strengthens a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon skipping (Houdayer_2012). The variant was absent in 251146 control chromosomes (gnomAD. c.5278-1G>C has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, particularly individuals affected with breast cancer (e.g., de la Hoya_2002, Rashid_2006, Houdayer_2012, Lang_2017, Arai_2018, Deng_2019, Rashid_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that a haploid human cell line harboring the variant and in which BRCA1 was essential showed complete loss of fitness (Findlay_2018). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077612	SCV000109415	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496568	SCV000587487	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077612	SCV001243039	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000077612	SCV002588834	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162419	SCV002758195	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research