Submissions for variant NM_007294.4(BRCA1):c.442-1G>T

gnomAD frequency: 0.00001  dbSNP: rs1351019392

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548280	SCV000635975	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (no rsID available, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). ClinVar contains an entry for this variant (Variation ID: 462651). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 7 (also known as exon 8 in the literature) (PMID: 24569164). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000663008	SCV000786017	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781007	SCV000918755	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.442-1G>T 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. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, while three predict the variant creates or strengthens an in-frame cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The ENIGMA Consortium recommends a reduced PVS1 evidence strength (PVS1_supporting) for variants altering this splice site, as they may result in functional in-frame transcripts that could rescue gene functionality. The variant allele was found at a frequency of 4e-06 in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442-1G>T has been reported in the literature in a study of patients with breast and/or ovarian cancer without strong evidence of causality (Bhaskaran_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 462651). Six submitters have classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001022460	SCV001184199	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The c.442-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 6 of the BRCA1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Canonical splice site variants are typically considered deleterious; however, alterations at this particular splice acceptor site result in a transcript with a predicted in-frame loss of a single amino acid at the beginning of coding exon 6 (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). This single amino acid loss is a naturally occurring isoform and may be referred to as Δ8p in some literature (Colombo M et al. Hum Mol Genet., 2014 Jul;23:3666-80). The functional and clinical significance of this single amino acid loss is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000663008	SCV001434978	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-12	criteria provided, single submitter	clinical testing	This c.442-1G>T variant in the BRCA1 gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. This variant has an extremely low frequency in large databases of genetic variation in the general population. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, this c.442-1G>T variant in the BRCA1 gene is classified as likely pathogenic.
GeneDx	RCV001837951	SCV002098205	uncertain significance	not provided	2022-02-09	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in aberrant splicing, potentially leading to a known naturally occurring isoform, the in-frame deletion of a single amino acid, p.Gln148del (Colombo 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 561-1G>T and IVS7-1G>T; This variant is associated with the following publications: (PMID: 27008870, 24569164, 30702160)
Sema4, Sema4	RCV001022460	SCV002537751	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000663008	SCV004037357	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-18	criteria provided, single submitter	clinical testing	The c.442-1G>T variant in the BRCA1 gene is a heterozygous canonical splice site variant, which affects an acceptor splice site in intron 6 (23 introns total; NM_007300.4). A substitution at this site is predicted to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Computational splicing tools have mixed results, where several predict the 3' acceptor site to be abolished, but also predict the strengthening of a cryptic 3' acceptor site that would only result in an in-frame deletion of several amino acids. There is some experimental data to show that the latter scenario may be true (PMID: 24569164). Currently, we do not definitively know which effect on the protein this variant will cause. This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/282,812), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this variant has not been reported in individuals affected with Hereditary Breast and Ovarian Cancer. Heterozygous loss-of-function variants in BRCA1, distal to this variant have been described to be associated with an increased risk of developing breast and ovarian cancer. However, the exact risk of breast and ovarian cancer, if any, conferred by this specific variant has not been determined.
Baylor Genetics	RCV000663008	SCV004215150	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-07	criteria provided, single submitter	clinical testing