rs876659992
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000059.4(BRCA2):c.7977-4_7977-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 splice_region, intron
NM_000059.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.29
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.7977-4_7977-3delTT | splice_region_variant, intron_variant | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7977-4_7977-3delTT | splice_region_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497.3 | ||||
| BRCA2 | ENST00000530893.7 | c.7608-4_7608-3delTT | splice_region_variant, intron_variant | 1 | ENSP00000499438.2 | |||||
| BRCA2 | ENST00000614259.2 | n.*35-4_*35-3delTT | splice_region_variant, intron_variant | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | BRCA2: PM2, BP4 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | The c.7977-4_7977-3delTT intronic variant, located in intron 16 of the BRCA2 gene, results from a deletion of two nucleotides within intron 16 of the BRCA2 gene. These nucleotide positions are well conserved in available vertebrate species. This variant, designated as c.7976-5_7976-4delTT, has been reported in an individual diagnosed with breast cancer at age 38 whose family history included both breast and ovarian cancers (Chen X et al. Hum. Mutat. 2006 May;27:427-35). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Although this alteration did not have any effect on splicing impact in one study, data were not shown (Chen X et al. Hum. Mutat. 2006 May;27:427-35). Internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The splice defect is similar to that observed in several close match alterations at the same acceptor site including c.7977-6T>G (Fraile-Bethencourt E et al. PLoS Genet., 2017 Mar;13:e1006691). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 09, 2019 | Variant summary: BRCA2 c.7977-4_7977-3delTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Chen_2006 reports this variant has no effect on splicing process. The variant was absent in 248894 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7977-4_7977-3delTT, has been reported in the literature in one proband whose family history of breast and/or ovarian cancer (Chen_2006). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6216delC , p.Leu2073TyrfsX8), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 06, 2022 | The BRCA2 c.7977-4_7977-3del intronic change results from the deletion of two non-conserved nucleotides at position 7944-4 to 7944-3 of intron 17 of the BRCA2 gene. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. RNA sequencing studies are not in agreement about the splicing effect of this variant (PMID: 16619214). This variant has been reported in an individual with a personal history of breast cancer and a family history of breast and ovarian cancer (PMID: 16619214). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
BRCA2-related cancer predisposition Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 22, 2024 | This variant causes a deletion of two nucleotides at the -4 and -3 position in intron 17 of the BRCA2 gene. An RNA study using carrier-derived RNA found this variant did not impact splicing (PMID: 16619214). This variant has been reported in individuals affected with early-onset breast cancer, with a family history of breast and ovarian cancer (PMID: 16619214). 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and family history of breast cancer and/or ovarian cancer (PMID: 16619214). ClinVar contains an entry for this variant (Variation ID: 232794). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant does not affect mRNA splicing (PMID: 16619214). 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. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at