13-32339385-GAA-GA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5035delA(p.Thr1679LeufsTer3) 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.5035delA | p.Thr1679LeufsTer3 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4666delA | p.Thr1556LeufsTer3 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5035delA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 44
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
Variant allele predicted to encode a truncated non-functional protein. -
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not provided Pathogenic:2
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; Identified in individuals with BRCA2-related cancers in published literature (Foley 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5263delA; This variant is associated with the following publications: (PMID: 26023681, 26845104, 29446198) -
This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families affected with breast/ovarian cancer (PMID: 11857748 (2002), 26023681 (2015), 35377489 (2022), 35710434 (2022)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 1 nucleotide 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 5263delA based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 26023681, 26845104), and has been identified in three 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.5035delA (p.T1679Lfs*3) alteration, located in coding exon 10 of the BRCA2 gene, consists of a deletion of one nucleotide at position 5035, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, referred to as 5263delA, was identified in female with a personal history of breast cancer at age 30 years (Foley, 2015). Based on the available evidence, this alteration is classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Thr1679Leufs*3) 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 cancers (PMID: 26023681, 26845104, 29446198). This variant is also known as 5263delA. ClinVar contains an entry for this variant (Variation ID: 37939). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.5035delA (p.Thr1679LeufsX3) 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 30916 control chromosomes (gnomAD). c.5035delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Foley_2015, Llort_2002, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not specified Pathogenic:1
The BRCA2 c.5035delA; p.Thr1679fs variant (rs80359477), also known as 5263delA, is reported in the literature in at least one individual affected with breast cancer (Foley 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37939), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Thr1679fs variant is considered to be pathogenic. References: Foley SB et al. Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. EBioMedicine. 2015 Jan;2(1):74-81. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
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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