rs1555282435
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000059.4(BRCA2):c.2093_2095delTAC(p.Leu698del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2093_2095delTAC | p.Leu698del | disruptive_inframe_deletion | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.1724_1726delTAC | p.Leu575del | disruptive_inframe_deletion | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.2093_2095delTAC | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461632Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727102
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
BRCA2-related cancer predisposition Uncertain:1
This variant causes an in-frame deletion of 1 amino acid, leucine at codon 698, in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders 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. -
Malignant tumor of breast Uncertain:1
The p.Leu698del variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD. This variant is an in-frame deletion resulting in the removal of a Leucine (Leu) residue at codon 698 and this residue is poorly conserved across mammals and other organisms; the impact of this alteration on BRCA2 protein function is not known. This variant was found in our laboratory to co-occur with a known pathogenic mutation, c.181T>G (p.Cys61Gly), increasing the likelihood that the p.Leu698del variant does not have clinical significance. 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 unknown significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.2093_2095delTAC variant (also known as p.L698del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame TAC deletion at nucleotide positions 2093 to 2095. This results in the in-frame deletion of a leucine at codon 698. This amino acid position is not 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This variant, c.2093_2095del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Leu698del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 433765). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at