Submissions for variant NM_007294.4(BRCA1):c.547+1G>A

dbSNP: rs80358030

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000112729	SCV000488302	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533400	SCV000636043	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 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 clinical features of hereditary breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 125881). 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, 23451180, 24667779). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570102	SCV000668385	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The c.547+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Close match alterations at the same canonical donor site, BRCA1 c.547+2T>A and BRCA2 c.547+1G>T, cause skipping of coding exon 6 (designated as exon 8 in the literature) which will produce an out-of-frame transcript with a predicted premature stop codon (Ambry internal data; Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Colombo M et al. PLoS ONE 2013 Feb;8:e57173). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000533400	SCV000699262	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.547+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. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251436 control chromosomes (gnomAD). c.547+1G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Mucaki_2011, Ryu_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21523855, 30350268, 31112363). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=1). One submitter cites internal data corroborating an impact of splicing. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001781438	SCV002023497	pathogenic	not provided	2019-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001781438	SCV004170181	pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing leading to out-of-frame skipping of exon 7, also known as exon 8, in a gene for which loss of function is a known mechanism of disease (Chevalier et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer (Ryu et al., 2019); Also known as 666+1G>A and IVS8+1G>A; This variant is associated with the following publications: (PMID: 21523855, 31112363, 32124385, 30350268)
Baylor Genetics	RCV000112729	SCV004212747	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570102	SCV004361106	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A similar canonical splice site variant, c.547+2T>A, at the intron 7 splice donor site has been shown to cause the out-of-frame skipping of exon 7, resulting in premature truncation and an absent or non-functional protein product (PMID: 10479726, 22505045, 23451180). This variant has been reported in an individual affected with triple-negative breast cancer (PMID: 30350268). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112729	SCV000145612	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing