rs276174852
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5065_5066delGCinsAAA(p.Ala1689LysfsTer6) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1689?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5065_5066delGCinsAAA | p.Ala1689LysfsTer6 | frameshift_variant, missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4696_4697delGCinsAAA | p.Ala1566LysfsTer6 | frameshift_variant, missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5065_5066delGCinsAAA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 2 nucleotides and inserts 3 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The c.5065_5066delGCinsAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from the deletion of two nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.A1689Kfs*6). This pathogenic mutation has been reported in one HBOC family (Lubinski J et al. Fam. Cancer. 2004;3:1-10). Of note, this mutation is also referred to as 5293delGCinsAAA in some literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Ala1689Serfs*6) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal and/or family history of BRCA2-related cancers (PMID: 15131399). This variant is also known as 5293delGCinsAAA . For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
This combined deletion and insertion is denoted BRCA2 c.5065_5066delGCinsAAA at the cDNA level and p.Ala1689LysfsX6 (A1689KfsX6) at the protein level. The surrounding sequence is TGAA[delGC][insAAA]AAAAAAAT. The variant causes a frameshift which changes an Alanine to a Lysine at codon 1689, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also published as BRCA2 5293delGCinsAAA using alternate nomenclature, this variant has been reported in at least one family with breast and/or ovarian cancer (Lubinski 2004). We consider BRCA2 c.5065_5066delGCinsAAA to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at