NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.1 ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in BRCA2 exon 11, where other proven pathogenic PTC variants have been established.2 The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.3 This variant has been classified as Pathogenic by the ENIGMA expert panel in ClinVar (Variation ID 51842), supported by 9 clinical laboratory submissions.4 Applying the ENIGMA Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong (PTC) (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) = 13 points, which reaches the Pathogenic threshold (>= 10 points).5
BRCA2
Final classification
Pathogenic
BRCA2 c.5344C>T · p.Gln1782Ter
BRCA2
NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong/PTC (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) + PP5_Supporting (Supporting = 1 point) = 14 points, meeting the Pathogenic threshold (>= 10 points). Also satisfies ENIGMA Table 3 all_of Pathogenic rule: 1 Very Strong + 1 Strong (PVS1 + PM5_Strong).
Classification rationale
PVS1PM2PM5PP5
Pathogenic
BRCA2 c.5344C>T
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 51842)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0368764.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 27 PMIDs triaged · 8 high-priority
27papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
10570174 ↗
functional
Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
BRCA2 mutations predispose carriers mainly to breast cancer. The vast majority of BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function. A series of green fluorescent protein (GFP)-ta
BS3PM1PS3
11239455 ↗
functional
BRCA2 is required for homology-directed repair of chromosomal breaks.
The BRCA2 tumor suppressor has been implicated in the maintenance of chromosomal stability through a function in DNA repair. In this report, we examine human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, we find th
BS3PM1PS3
20878484 ↗
functional
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
Heterozygous germ line mutations in the Breast CAncer1 (BRCA1) and BRCA2 genes can lead to a high risk of breast and ovarian cancer, in addition to a significantly increased susceptibility of pancreatic, prostate and male breast cancer. The BRCA2 belongs to the tumor suppressor gene family and the protein encoded by this gene is involved in the repair of chromosomal damage, with an important role
BS3PM1PS3
22193408 ↗
functional
BRCA1 and BRCA2: different roles in a common pathway of genome protection.
The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous
BS3PM1PS3
24312913 ↗
functional
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the popul
BS3PM1PS3
20104584 ↗
functional
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of wh
BS3PP5PS3PS4
23918944 ↗
splicing rna
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familia
BP7PP3PP5PS4PVS1
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PS3PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links