rs786202381
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000059.4(BRCA2):c.5272_5274delAAT(p.Asn1758del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.5272_5274delAAT | p.Asn1758del | conservative_inframe_deletion | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4903_4905delAAT | p.Asn1635del | conservative_inframe_deletion | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5272_5274delAAT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250330Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135464
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1459842Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 726312
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
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Hereditary cancer-predisposing syndrome Uncertain:2
The c.5272_5274delAAT variant (also known as p.N1758del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame AAT deletion at nucleotide positions 5272 to 5274. This results in the in-frame deletion of an asparagine at codon 1758. This alteration has been identified, in conjunction with a BRCA1 deletion, in one patient from a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). 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. -
This variant causes an in-frame deletion of one amino acid at codon 1758 in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 24549055, 27495310). This variant has been identified in 6/281730 chromosomes 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
Variant summary: The BRCA2 c.5272_5274delAAT (p.Asn1758del) variant causes a missense change involving the alteration of a non-conserved nucleotide. One in silico tool predicts a disease-causing outcome for this variant. The variant is absent in 120396 control chromosomes within ExAC control database. Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. UMD database found this variant co-occurring with a pathogenic variant in BRCA1 (c.442-4357del; p.Glu149TyrfsX2) and classified it as a VUS. Because of the paucity of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Familial cancer of breast Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This variant, c.5272_5274del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Asn1758del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587780655, gnomAD 0.004%). This variant has been observed in individual(s) with breast or ovarian cancer (PMID: 24549055, 27495310). ClinVar contains an entry for this variant (Variation ID: 185693). 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. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at