rs80359630
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.700delT(p.Ser234ProfsTer7) 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.700delT | p.Ser234ProfsTer7 | frameshift_variant | Exon 9 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.331delT | p.Ser111ProfsTer7 | frameshift_variant | Exon 9 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.700delT | non_coding_transcript_exon_variant | Exon 8 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
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Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
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Variant summary: BRCA2 c.700delT (p.Ser234ProfsX7) 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. The variant was absent in 250024 control chromosomes (gnomAD). c.700delT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Nedelcu_2002, Giannini_2006, Seong_2009, Kluska_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Ser234Profs*7) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 11938448, 19656164, 22762150, 22798144, 26843898). This variant is also known as 924delT or 928delT. ClinVar contains an entry for this variant (Variation ID: 38079). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
The p.Ser234ProfsX7 deletion variant was identified in 4 of 6352 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Capalbo 2006, Kim 2012, Meindl 2002, Nedelcu 2002). The variant was also identified in dbSNP (ID: rs80359630) “With Pathogenic allele”, HGMD, ClinVar database, the BIC database (3X with clinical importance), and UMD (6X as a causal variant). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Ser234ProfsX7 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 234 and leads to a premature stop codon 7 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Nedelcu 2002, Lubinski 2004, Giannini 2006, Sinilnikova 2006, Seong 2009, Kim 2012, Germani 2018; Also known as 924delT and 928delT; This variant is associated with the following publications: (PMID: 15131399, 11938448, 16847550, 16528604, 26843898, 22798144, 19656164, 25948282, 22762150, 30263092, 31921681) -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.700delT pathogenic mutation, located in coding exon 8 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 700, causing a translational frameshift with a predicted alternate stop codon. This mutation has been previously identified in Italian, German, and Korean breast/ovarian cancer cohorts (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80; Capalbo C et al. Ann. Oncol., 2006 Jun;17 Suppl 7:vii34-40; Seong MW et al. Clin. Genet., 2009 Aug;76:152-60). Of note, this alteration has also been designated as 928delT 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. -
This variant deletes 1 nucleotide in exon 9 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 has been reported in at least six individuals affected with breast cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 11802209, 11938448, 16760289, 19656164, 22762150, 26843898). 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. -
Breast and/or ovarian cancer Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at