Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_007294.4(BRCA1):c.671-1G>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 0.61266094 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 17-43094861-C-A is Pathogenic according to our data. Variant chr17-43094861-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125908.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=3}. Variant chr17-43094861-C-A is described in Lovd as [Pathogenic].
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Nov 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.671-1G>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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of BRCA1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 236750 control chromosomes (gnomAD). c.671-1G>T has been reported in the literature in individuals affected with hereditary breast and ovarian cancer syndrome (example: Mannan_2016, Rebbeck_2018, Tuncer_2024, Zhang_2022). These data indicate that the variant is likely to 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: 36660366, 26911350, 29446198, 38219492, 35918668). ClinVar contains an entry for this variant (Variation ID: 125908). Based on the evidence outlined above, the variant was classified as pathogenic. -
Jul 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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 a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 125908). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Familial cancer of breast Pathogenic:1
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Center for Precision Medicine, Meizhou People's Hospital
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.671-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 9 of the BRCA1 gene. This alteration was identified in an Asian Indian individual diagnosed with breast cancer at age 38, whose sister and grandmother were also diagnosed with breast cancer (Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). This nucleotide position is completely conserved on sequence alignment in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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
Aug 24, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28726806, 29446198, 29470806, 28152038, 21523855, 12960223, 26911350, 31131967) -