rs80359577
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6373del(p.Thr2125ProfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E2123E) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.6373del | p.Thr2125ProfsTer12 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6373del | p.Thr2125ProfsTer12 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1453234Hom.: 0 Cov.: 44 AF XY: 0.00000277 AC XY: 2AN XY: 722624
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 22, 2010 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2019 | Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and has been described as a pathogenic founder variant in the Danish population (Hkansson 1997, Thomassen 2008, Janavicius 2010, Nielsen 2016, Roed Nielsen 2016, Sharma 2016); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 6601delA; This variant is associated with the following publications: (PMID: 23199084, 26004055, 24312913, 26360800, 9150154, 18465347, 26833046, 30322717, 31263571) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.6373delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6373, causing a translational frameshift with a predicted alternate stop codon (p.T2125Pfs*12). This mutation has been reported in Scandinavian and Danish breast and ovarian cancer families and is a well known founder mutation in the Danish population (Håkansson S et al. Am. J. Hum. Genet. 1997 May;60:1068-78; Nielsen HR et al. Fam. Cancer 2016 Oct;15:507-12; Thomassen M et al. Acta Oncol 2008;47:772-7; Janaviius R. EPMA J 2010 Sep;1:397-412). This mutation has also been reported in a patient diagnosed with pancreatic cancer at age 35 (Sharma MB et al. Acta Oncol 2016 May;55:377-81). In addition, this alteration was identified in 44 families in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 6601delA in published 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | 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 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. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52075). This variant is also known as 6601delA. This premature translational stop signal has been observed in individual(s) with prostate and breast cancer (PMID: 9150154, 18465347, 26004055, 26360800). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr2125Profs*12) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at