rs587782157
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PM4_Supporting
The NM_000059.4(BRCA2):c.4141_4143delAAA(p.Lys1381del) variant causes a conservative 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K1381K) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 conservative_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.4141_4143delAAA | p.Lys1381del | conservative_inframe_deletion | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.3772_3774delAAA | p.Lys1258del | conservative_inframe_deletion | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.4141_4143delAAA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1456864Hom.: 0 AF XY: 0.00000414 AC XY: 3AN XY: 724332
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
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. -
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. -
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not specified Uncertain:1
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
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
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
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
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Hereditary breast ovarian cancer syndrome Uncertain:1
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. 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: 141985). 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