rs80359576
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6352_6353delGT(p.Val2118LysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6352_6353delGT | p.Val2118LysfsTer10 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5983_5984delGT | p.Val1995LysfsTer10 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6352_6353delGT | 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:4
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Variant allele predicted to encode a truncated non-functional protein. -
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 6580delGT based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 14574155, 16615107, 24156927). This variant has also been identified in two families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -
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not provided Pathogenic:2
This deletion of 2 nucleotides in BRCA2 is denoted c.6352_6353delGT at the cDNA level and p.Val2118LysfsX10(V2118KfsX10) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTGT[GT]AAAC. The deletion causes a frameshift, which changes a Valine to a Lysine at codon 2118, and creates a premature stop codon at position 10 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. BRCA2 c.6352_6353delGT, also reported as BRCA2 6580delGT using alternate nomenclature, has been reported in individuals with familial breast and/or ovarian cancer (Piek 2003, Tea 2014). We consider this variant to be pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 6580delGT in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 14574155, 16615107, 24156927, 36853301). This variant has also been identified in two families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.6352_6353delGT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6352 and 6353, causing a translational frameshift with a predicted alternate stop codon (p.V2118Kfs*10). This alteration has been previously identified in several breast/ovarian cohorts (Piek JM et al. Fam. Cancer. 2003;2:73-8; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). Of note, this alteration is also designated 6580delGT in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.Val2118Lysfs*10) 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 breast or ovarian cancer (PMID: 14574155, 24156927). This variant is also known as 6580delGT. ClinVar contains an entry for this variant (Variation ID: 52071). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.6352_6353delGT (p.Val2118LysfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245524 control chromosomes and c.6352_6353delGT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Piek_2003, Hermsen_2006, Tea_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories, one expert panel, and one consortium have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
BRCA2-related disorder Pathogenic:1
The BRCA2 c.6352_6353delGT variant is predicted to result in a frameshift and premature protein termination (p.Val2118Lysfs*10). This variant was reported in individuals with breast cancer or ovarian cancer (Tea MK et al 2013. PubMed ID: 24156927; Lilyquist J et al 2017. PubMed ID: 28888541; Ravichandran V et al 2019. PubMed ID: 30787465; Rebbeck TR et al 2018. PubMed ID: 29446198). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52071/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at