Submissions for variant NM_007294.4(BRCA1):c.5277+1G>A

dbSNP: rs80358150

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031235	SCV000244394	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	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 = 1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000074601	SCV000076909	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast or ovarian cancer (PMID: 11149413, 16683254, 19949876). ClinVar contains an entry for this variant (Variation ID: 37654). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that disruption of this splice site results in activation of a cryptic splice site in intron 19 or skipping of exon 19 (also known as exon 20) and introduces a premature termination codon (PMID: 24667779; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235135	SCV000108686	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in an in-frame deletion of a critical region (Tesoriero 2005, Sanz 2010, Steffensen 2014); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay 2018); Not observed in large population cohorts (Lek 2016); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson 2014); Observed in individuals with early-onset or familial breast and/or ovarian cancer (de la Hoya 2001, Diez 2003, van Harssel 2010, Lara 2012); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar SCV000244394.1; Landrum 2016); Also known as 5396+1G>A or IVS20+1G>A; This variant is associated with the following publications: (PMID: 23348723, 23096355, 19593635, 20215541, 19949876, 18286383, 18528753, 25849179, 18298804, 26913838, 29446198, 17924331, 21990134, 25525159, 11149413, 12955716, 16211554, 25859162, 24667779, 28636540, 28477318, 28918466, 30209399, 30720863, 25085752, 32665702)
Ambry Genetics	RCV000131865	SCV000186920	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The c.5277+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the BRCA1 gene. This mutation has been identified in multiple breast and/or ovarian cancer families (de la Hoya M et al. Int. J. Cancer. 2001 Jan;91:137-40; Verhoog LC et al. Eur. J. Cancer. 2001 Nov;37:2082-90; Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Díez O et al Hum. Mutat. 2003 Oct;22:301-12; Piek JM et al. Fam. Cancer. 2003;2:73-8; Lara K et al. Biol. Res. 2012;45:117-30). This alteration has been classified as definitely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Multiple RNA studies have demonstrated that this alteration results in abnormal splicing (Tesoriero AA et al. Hum. Mutat. 2005 Nov;26:495; Elstrodt F et al. Cancer Res. 2006 Jan;66:41-5; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8; Tesoriero AA et al. Hum. Mutat. 2014 Apr;35:511; Ambry internal data). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this mutation is also designated as IVS20+1G>A and 5396+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	RCV000031235	SCV000220602	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-08-19	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000131865	SCV000292160	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the BRCA1 gene. This variant is also known as IVS20+1G>A by a legacy nomenclature in the literature. RNA studies have found that this variant results in the retention of 87 nucleotides from intron 19 and the skipping of exon 19, that are predicted to cause in-frame insertion of 29 amino acids in the BRCT domain and out-of-frame splicing, respectively (PMID: 16211554, 24667779, 31843900). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in several individuals affected with breast or ovarian cancer, one individual affected with peritoneal cancer (PMID: 14574155, 16211554, 20215541, 21913181, 23096355) and in at least four dozen suspected hereditary breast and ovarian cancer families (PMID: 11149413, 11597388, 11802209, 16683254, 19949876, 24285858), including one family in which this variant segregates with ovarian cancer in five members of one family (PMID: 16211554). This variant also has been detected in a breast cancer case-control meta-analysis in 8/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000441). A multifactorial analysis has reported a family history likelihood ratio for pathogenicity of 11.1 (PMID: 17924331). 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	RCV000235135	SCV000296332	pathogenic	not provided	2015-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031235	SCV000326234	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507129	SCV000602686	pathogenic	not specified	2017-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074601	SCV000699231	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5277+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 5' splicing donor site. These predictions have been confirmed by experimental evidence showing the variant to result in the skipping of exon 20 and generating a truncated protein (Tesoriero_2005). The variant was absent in 251494 control chromosomes. c.5277+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg Meindl_2002, Diez_2003, Tesoriero_2012, Lara_2012, Litton_2012, Brohet_2014, etc). 12 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031235	SCV000743373	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031235	SCV000744588	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235135	SCV002020145	pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000074601	SCV002515230	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Baylor Genetics	RCV000031235	SCV004215054	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031235	SCV004834029	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-19	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the BRCA1 gene. This variant is also known as IVS20+1G>A by a legacy nomenclature in the literature. RNA studies have found that this variant results in the retention of 87 nucleotides from intron 19 and the skipping of exon 19, that are predicted to cause in-frame insertion of 29 amino acids in the BRCT domain and out-of-frame splicing, respectively (PMID: 16211554, 24667779, 31843900). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in several individuals affected with breast or ovarian cancer, one individual affected with peritoneal cancer (PMID: 14574155, 16211554, 20215541, 21913181, 23096355) and in at least four dozen suspected hereditary breast and ovarian cancer families (PMID: 11149413, 11597388, 11802209, 16683254, 19949876, 24285858), including one family in which this variant segregates with ovarian cancer in five members of one family (PMID: 16211554). This variant also has been detected in a breast cancer case-control meta-analysis in 8/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000441). A multifactorial analysis has reported a family history likelihood ratio for pathogenicity of 11.1 (PMID: 17924331). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000031235	SCV005042909	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The invariant splice donor c.5277+1G>A variant in BRCA1 gene has been reported previously in heterozygous state in multiple individuals affected with Hereditary Breast and/or Ovarian cancer Steffensen AY, et al., 2014; van Harssel JJ, et al., 2010; van der Hout AH, et al., 2006. This variant has been known to segregate with disease. Functional studies indicate that this variant leads to skipping of exon 20 and creates a premature stop codon, proving a damaging effect Tesoriero AA, et al., 2005. The c.5277+1G>A variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031235	SCV000053836	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031235	SCV000145422	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000074601	SCV000587485	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353526	SCV000591605	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.5277+1G>A variant has been previously reported in the literature in at least 5 of 3526 proband chromosomes in individuals with hereditary breast and ovarian cancer (De La Hoya 2001, Sanz 2010, Diez 2003, Easton 2007, Tesoriero 2005). In one study, bilateral breast cancer was noted and the presence of other cancers in the family (Diez 2003). In two studies, disease status was noted in 6 individuals (1 with breast and 5 with ovarian) and the variant was shown to segregate with disease in at least one affected family member (Sanz 2010, Tesoriero 2005). Tesoriero et al. (2005) carried out functional studies and determined that this variant leads to two alternative products, one causing exon 20 skipping and leading to a premature stop codon at codon 1737 and the other having retention of exon 20 and leading to a stop codon at codon 1767. The variant was identified in the UMD database 3 times as causal and in the BIC database 43 times as being clinically important. Easton et al (2007) report this variant as having >10e11 odds in favour of causality. Furthermore, this variant occurs within the +1 position of the 3' consensus splice site and variants at this position are a known mechanism of mutation and the type of variant expected to cause the disorder. In addition, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 5 of 5 different programs. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031235	SCV000733590	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131865	SCV000787910	pathogenic	Hereditary cancer-predisposing syndrome	2017-10-30	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735562	SCV000863700	pathogenic	Breast and/or ovarian cancer	2016-01-22	no assertion criteria provided	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000235135	SCV000925675	not provided	not provided		no assertion provided	in vitro
Brotman Baty Institute, University of Washington	RCV000031235	SCV001242994	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
King Laboratory, University of Washington	RCV001171438	SCV001251349	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000235135	SCV001906442	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235135	SCV001955091	pathogenic	not provided		no assertion criteria provided	clinical testing