Submissions for variant NM_007294.4(BRCA1):c.5075-1G>A

dbSNP: rs1800747

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480623	SCV000564746	pathogenic	not provided	2018-06-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5075-1G>A or IVS16-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 16 of the BRCA1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also known as BRCA1 5194-1G>A and IVS17-1G>A using alternate nomenclature, has been reported in individuals suspected of having hereditary breast/ovarian cancer as well as in at least one individual with metastatic prostate cancer (Jara 2006, Pritchard 2016, Apessos 2018, Wang 2018). We consider this variant to be pathogenic.
Yang An-Suei Laboratory, Academia Sinica	RCV000504600	SCV000575770	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Counsyl	RCV000112485	SCV000677656	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579615	SCV000683249	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 16 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in three individuals affected with breast cancer (PMID: 16616110; Color internal data) and additional families suspected of hereditary breast and ovarian cancer (PMID: 12402332, 29310832, 29566657). Other canonical splice acceptor site variants in intron 16 have been reported as disease-causing in ClinVar (variation ID 55378, 55379, 55380, 125759, 252381) and reported in individuals or families affected with breast or ovarian cancer (PMID: 29446198, 30287823). 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 Likely Pathogenic.
GeneKor MSA	RCV000585700	SCV000693543	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a substitution of the last nucleotide of intron 17 of the BRCA gene. This particular position is highly conserved in human as well as in other genomes. It is expected that this variant affects the correct mRNA splicing and results in the deletion of an entire exon. This causes the formation of a truncated non functional protein. This mutation has been described in breast cancer patients (PMID: 16616110). This particular variant has been described in the mutation database ClinVar (Variation ID: 55377/)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496384	SCV000966916	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-01	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
CeGaT Center for Human Genetics Tuebingen	RCV000480623	SCV001501175	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000496384	SCV001585896	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 of the BRCA1 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 BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 12402332, 27433846, 29566657). This variant is also known as IVS17-1G>A. ClinVar contains an entry for this variant (Variation ID: 55377). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000112485	SCV004215189	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-14	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112485	SCV000145296	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-22	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496384	SCV000587455	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112485	SCV001244048	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro