Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_Strong
The NM_007294.4(BRCA1):c.670+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.2, offset of -1, new splice context is: aagGTtaat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 05, 2023
The c.670+1G>T intronic variant, referred to as IVS10+1G>T in some literature, results from a G to T substitution one nucleotide after coding exon 8 (also known as exon 10 in some literature) of the BRCA1 gene. This alteration is located at the canonical splice donor site which is skipped in one of the natural in-frame minor isoforms (known in the literature as BRCA1 delta 9-10) (Colombo M et al. Hum Mol Genet. 2014; 23:3666-80). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor 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, in BRCA1, the pathogenicity of alterations at canonical splice sites of exons that are skipped in the naturally occurring delta 9-10 in-frame minor isoform have yet to be determined, as they may be partially functional (de la Hoya M et al. Hum. Mol. Genet. April 2016). As such, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 29, 2022
This variant causes a G to T nucleotide substitution at the +1 position of intron 9 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, splice donor variants at positions +1 and +2 are expected to result in an absent or disrupted protein product. However, the naturally-occurring and functional alternative BRCA1 transcript lacking exons 8 and 9 is thought to ameliorate canonical splice site variants in exons 8 and 9 (PMID: 19892845, 27008870). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Dec 21, 2009
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Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided
research
Laboratory for Genotyping Development, RIKEN
Jul 01, 2021
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Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Sep 12, 2023
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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 24569164, 24667779, 27008870; Invitae). ClinVar contains an entry for this variant (Variation ID: 91661). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). -