Submissions for variant NM_007294.4(BRCA1):c.4675+1G>A

dbSNP: rs80358044

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)	RCV000077582	SCV000244367	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	RCV000225764	SCV000076636	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 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 and/or ovarian cancer (PMID: 12491499, 21324516, 23767878, 24884479). This variant is also known as IVS15+1G>A and 4794+1G>A. ClinVar contains an entry for this variant (Variation ID: 55256). 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: 21990134). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18489799, 21394826; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131822	SCV000186877	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The c.4675+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the BRCA1 gene. This mutation has been detected in multiple breast and ovarian cancer families (Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Adem C et al. Cancer. 2003 Jan;97:1-11; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38(6):361-8; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). RNA studies have demonstrated that this alteration results in exon skipping of coding exon 13 and/or use of a cryptic donor site resulting in the loss of 11nt of exon 13 (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8; Machackova E et al. BMC Cancer. 2008 May;8:140). Based on multifactorial probability modeling, the posterior probability of this mutation being deleterious was calculated to be 1.00 (Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 pathogenic.
GeneDx	RCV000048623	SCV000210184	pathogenic	not provided	2019-10-28	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 11389159, 24667779, 26295337, 29452958, 29907814, 21895635, 21394826, 18712473, 21324516, 21990134, 21965345, 25525159, 12491499, 17924331, 23239986, 18489799, 26913838, 28324225, 27914478, 26976419, 25085752, 24884479, 20104584, 29161300, 30078507, 29446198, 30322717, 29470806, 26848151, 31263571)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048623	SCV000296399	pathogenic	not provided	2019-10-30	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 patient with expected phenotype for this gene, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077582	SCV000326016	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414441	SCV000492461	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Mendelics	RCV000225764	SCV000839229	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762997	SCV000893442	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131822	SCV000911174	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 14 of the BRCA1 gene. Functional RNA studies have shown that this variant causes skipping of exon 14 (also known as exon 15 in the literature), resulting in frameshift and premature truncation (PMID: 18489799, 21394826, 24667779). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12491499, 18489799, 21324516, 23767878, 27914478, 28324225). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000330). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000048623	SCV001247347	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077582	SCV001429302	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-09-16	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000048623	SCV002009437	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000048623	SCV002502347	pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000077582	SCV003807336	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated
Revvity Omics, Revvity	RCV000048623	SCV003818004	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077582	SCV004021934	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 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) nor in our local database. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12491499, 18489799, 21324516, 23767878, 27914478, 28324225). ClinVar contains an entry for this variant (Variation ID: 55256) with 21 submissions, all of which describe it as pathogenic, three stars, reviewed by expert panel.  .In silico, predict that this variant has a high probability of being pathogenic (PMID: 21990134). Studies have shown that disruption of this splice site results in exon skipping introduces a premature termination codon (PMID: 18489799, 21394826). For these reasons, this variant has been classified as Pathogenic. ​​​​​​​
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048623	SCV004026758	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077582	SCV004216905	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-09-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077582	SCV004822553	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 14 of the BRCA1 gene. Functional RNA studies have shown that this variant causes skipping of exon 14 (also known as exon 15 in the literature), resulting in frameshift and premature truncation (PMID: 18489799, 21394826, 24667779). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12491499, 18489799, 21324516, 23767878, 27914478, 28324225). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000330). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000225764	SCV004848396	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The c.4675+1G>A variant in BRCA1 has been reported in over 60 individuals with BRCA1-related cancer (Adem 2003 PMID: 12491499 and at least 17 subsequent publications). It was absent from large population studies. This variant was classified as pathogenic on 08/10/15 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55256). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Two additional variants, c.4675+1G>C and c.4675+1G>T, resulting in the same splice site interruption, have been identified in individuals with HBOC and are classified as pathogenic by ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Strong, PP3.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077582	SCV005045972	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1 (RNA); PM2_Supporting; PP1
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000048623	SCV005199713	pathogenic	not provided	2023-10-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077582	SCV000109385	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-07-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077582	SCV000145144	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000225764	SCV000587418	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735555	SCV000863693	likely pathogenic	Breast and/or ovarian cancer	2010-10-26	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077582	SCV002588815	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000077582	SCV004041662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-09	no assertion criteria provided	clinical testing