Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_007294.4(BRCA1):c.671-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.61248213 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43094862-T-C is Pathogenic according to our data. Variant chr17-43094862-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 267617.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=2}. Variant chr17-43094862-T-C is described in Lovd as [Likely_pathogenic].
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
May 05, 2022
Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 24212087). This variant disrupts the nuclear localization signal, DNA binding domain and coiled-coil domain of BRCA1, which mediate interactions with RAD51, RAD50 and PALB2 (PMID: 25652403, 22737296). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 267617). This sequence change affects an acceptor splice site in intron 9 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 personal and/or family history of breast and/or ovarian cancer (PMID: 22711857, 26689913, 29446198). -
Likely pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Nov 21, 2019
Variant Summary: BRCA1 c.671-2A>G 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 3' acceptor site. Several publications report experimental evidence that this variant affects mRNA splicing with the most recent one confirming this observation utilizing RNA in situ hybridization to measure the absolute expression of BRCA1 mRNA splicing events in single lymphoblastoid cells containing this variant (Whiley_2014, Lattimore_2018, and Lattimore_2019). The variant was absent in 236750 control chromosomes. c.671-2A>G has been reported in at-least one individual the literature in a sequencing study of Australian women affected with Ovarian Cancer (Alsop_2012). This patient is also cited in the kConfab and Leiden Open Source variation databases and immortalized lymphoblastoid cell lines derived from this carrier were utilized in subsequent studies. In the absence of co-segregation studies, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic using overlapping evidences utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical cases of patients and families with this variant are reported, it was re-classified as likely pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 02, 2021
The c.671-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in 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 acceptor site. 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; however this exon, which comprises over 50% of the BRCA1 protein, is absent in part or in whole in naturally occurring alternative splicing isoforms (Colombo M et al. Hum Mol Genet 2014 Jul;23(14):3666-80). Functional studies have shown that loss of this exon may impair cellular localization and have reduced, but not lost, DNA damage repair function (Thakur S et al. Mol Cell Biol 1997 Jan;17(1):444-52, Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15, Kim SS et al. Mol Cell Biol 2006 Sep;26(18):6983-92). Additionally, mouse embryos with homozygous BRCA1 coding exon 9 deletions survive longer than BRCA1-null embryos, suggesting protein without exon 9 may still be able to perform some BRCA1 essential functions (Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15). Based on the majority of available evidence to date, this variant is likely pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 05, 2020
Canonical splice site variant resulting in multiple different transcripts, including full-length, in-frame deletion of exon 10, also known as exon 11 by alternate numbering, and various out-of-frame isoforms (Whiley 2014, Lattimore 2018, Lattimore 2019); Observed in individuals with ovarian cancer (Alsop 2012); Not observed in large population cohorts (Lek 2016); Also known as 790-2A>G or IVS10-2A>G; This variant is associated with the following publications: (PMID: 29774201, 20167696, 22711857, 30736279, 31131967, 24212087, 29446198) -