rs397507971
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000059.4(BRCA2):c.8258_8260delTTC(p.Leu2753del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000656 in 152,324 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.8258_8260delTTC | p.Leu2753del | disruptive_inframe_deletion | Exon 18 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7889_7891delTTC | p.Leu2630del | disruptive_inframe_deletion | Exon 18 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*316_*318delTTC | non_coding_transcript_exon_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*316_*318delTTC | 3_prime_UTR_variant | Exon 17 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248884Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134702
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74480
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:1Other:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The c.8258_8260delTTC variant (also known as p.L2753del) is located in coding exon 17 of the BRCA2 gene. This variant results from an in-frame deletion of TTC at nucleotide positions 8258 to 8260. This results in the in-frame deletion of a leucine at codon 2753. One group has reported that this alteration may have an impact on splicing, as the variant modified the alternative splicing of exon 18 (coding exon 17), however transcripts lacking this exon were also present in controls, therefore the clinical consequences of this finding could not be conclusively determined based on this study (Bonnet C et al. J. Med. Genet., 2008 Jul;45:438-46; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This nucleotide region is not well conserved in available vertebrate species. In addition, the in silico prediction for the single amino acid deletion resulting from this alteration is inconclusive (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.8258_8260del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Leu2753del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779336144, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 18424508). This variant is also known as c.8257_8259delCTT (p.Leu2753del). ClinVar contains an entry for this variant (Variation ID: 52539). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 18424508). 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