13-32341112-CTT-CT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6762del(p.Phe2254LeufsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 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. L2253L) 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.6762del | p.Phe2254LeufsTer26 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6762del | p.Phe2254LeufsTer26 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461626Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727128
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 245827). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe2254Leufs*26) 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2018 | Variant summary: BRCA2 c.6762delT (p.Phe2254LeufsX26) 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 (eg. c.6944_6947delTAAA, p.Ile2315fsX12; c.6952C>T, p.Arg2318X; c.6997_6998delGT, p.Val2333fsX6). The variant was absent in 121018 control chromosomes. To our knowledge, no occurrence of c.6762delT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. This lab has reported the variant to be in cis with the pathogenic BRCA2 variant c.6816_6841+1534del1560, a large deletion which occurs prior to the location of the current variant of interest, indicating the BRCA2 c.6762delT possibly is not expected to be clinically significant in the individual or family reported by this lab. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Dec 15, 2017 | Variant allele predicted to encode a truncated non-functional protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2015 | This deletion of one nucleotide in BRCA2 is denoted c.6762delT at the cDNA level. The normal sequence, with the base that is deleted in braces, is CTTTT[T]ACAT. This variant has not, to our knowledge, been reported in the literature. Of note, BRCA2 c.6762delT is known to be in cis with the pathogenic BRCA2 variant, c.6816_6841+1534del1560. The BRCA2 c.6762delT deletion would be expected to cause a frameshift leading to a premature stop codon. However, the large deletion c.6816_6841+1534del1560 occurs prior to the location of the premature stop codon. Thus, BRCA2 c.6762delT is not expected to be clinically significant in this individual or family., - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at