rs80359261
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1054dupT(p.Tyr352LeufsTer6) 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.1054dupT | p.Tyr352LeufsTer6 | frameshift_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.685dupT | p.Tyr229LeufsTer6 | frameshift_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.1054dupT | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
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:4
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This sequence change creates a premature translational stop signal (p.Tyr352Leufs*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 a personal and/or family history of breast and/or ovarian cancer (PMID: 25428384, 26941049, 28831036). This variant is also known as 1282insT. ClinVar contains an entry for this variant (Variation ID: 37725). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.1054dupT (p.Tyr352LeufsX6) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247576 control chromosomes (gnomAD). c.1054dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29446198). Ten submitters (including ENIGMA expert panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:3
PVS1, PM2, PP4, PP5 -
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 (gnomAD); Observed in individuals with a personal and/or family history including breast, ovarian, and other cancers in published literature (Sinclair et al., 2002; Rashidi et al., 2015; Dos Santos Vidal et al., 2016; Maxwell et al., 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1282dupT; This variant is associated with the following publications: (PMID: 12097257, 26941049, 25428384, 28831036, 28152038, 30787465, 29446198, 20104584, 32885271, 35944511) -
The BRCA2 c.1054dup (p.Tyr352Leufs*6) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with a personal or family history of breast cancer (PMIDs: 28831036 (2017), 26941049 (2016), 12097257 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1054dupT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of T at nucleotide position 1054, causing a translational frameshift with a predicted alternate stop codon (p.Y352Lfs*6). This mutation has been reported multiple individuals with breast cancer (Rashidi A et al. Med. Oncol. 2015 Jan;32:371; Maxwell KN et al. Nat. Commun. 2017 08;8(1):319), as well as large cohorts of individuals who underwent BRCA1/2 testing (Dos Santos Vidal R et al. J Mol Diagn, 2016 05;18:362-369; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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 inserts 1 nucleotide in exon 10 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 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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Malignant tumor of breast Pathogenic:1
The BRCA2 p.Tyr352Leufs*6 variant was identified in 6 of 61698 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Dos Santos Vidal 2016, Maxwell 2017, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359261) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seven other submitters; as likely pathogenic by Counsyl), and LOVD 3.0 (2x as pathogenic). The variant was not identified in the UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1054dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 352 and leads to a premature stop codon at position 357. 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 (HBOC) 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. -
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