rs587782157
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000059.4(BRCA2):βc.4141_4143delβ(p.Lys1381del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000549 in 1,456,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 inframe_deletion
NM_000059.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.11
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4141_4143del | p.Lys1381del | inframe_deletion | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4141_4143del | p.Lys1381del | inframe_deletion | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1456864Hom.: 0 AF XY: 0.00000414 AC XY: 3AN XY: 724332
GnomAD4 exome
AF:
AC:
8
AN:
1456864
Hom.:
AF XY:
AC XY:
3
AN XY:
724332
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 25, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2024 | The c.4141_4143delAAA variant (also known as p.K1381del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 4141 through 4143. This results in the deletion of a lysine residue at codon 1381. The deleted amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | This variant causes an in-frame deletion of 1 amino acid in exon 11 of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.102 and 0.247, respectively (PMID: 31131967). 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2023 | Variant summary: BRCA2 c.4141_4143delAAA (p.Lys1381del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 245496 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4141_4143delAAA was reported in a hereditary breast cancer patient sample, however, the variant was designated as a false postivie for a different true indel (c.4146_4148delAGA; Bosdet_2013). The variant was also previously identified in a BRCA1/BRCA2 sequencing dataset, however, no genotype-phenotype, co-occurrence, or co-segregation data was provided; in these studies, in silico analyses predicted the variant to be neutral and likely benign (Parsons_2019, Cline_2019, Padilla_2019). These reports do not provide 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. Five 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 uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2023 | This variant causes an in-frame deletion of 1 amino acid in exon 11 of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.102 and 0.247, respectively (PMID: 31131967). 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. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2024 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published functional study demonstrates proficient homologous recombination (PMID: 38398132); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.4369_4371delAAA; This variant is associated with the following publications: (PMID: 24094589, 31131967, 38398132) - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Lys1381del variant was identified in 1 of 182 proband chromosomes (frequency: 0.005) from individuals or families with hereditary breast and ovarian cancer (Bosdet 2013). However, this study found that this genome position reproducibly generated false-positive results in all downsampling experiments and was excluded from the analysis (Bosdet 2013). They found the variant flanks a true indel c.4146_4148delAGA (Bosdet 2013). The variant was also identified in dbSNP (ID:rs587782157) with "uncertain significance allele," ClinVar (uncertain significance by GeneDx and Ambry Genetics), Clinvitae, LOVD 3.0 (3x), and UMD-LSDB (2x as uncertain significance). The variant was not identified in Cosmic, MutDB, BIC Database, ARUP Laboratories, or the Zhejiang Colon Cancer database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 1381; the impact of this alteration on BRCA2 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 24, 2023 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 29, 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 141985). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.4141_4143del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Lys1381del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at