The BRCA2 c.8242G>A (p.Gly2748Ser; G2748S) variant has been reported in ClinVar, where the current expert-panel overall classification is uncertain significance, while multiple clinical laboratory submissions classify it as likely pathogenic or pathogenic.1 This variant is present at very low frequency in population databases, including gnomAD v2.1 at 3/249070 alleles (AF 1.20e-05; grpmax FAF 9.58e-06) and gnomAD v4.1 at 6/1614064 alleles (AF 3.72e-06), which is below ENIGMA BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.2 In the ENIGMA BRCA2 functional evidence table, this exact variant is assigned PS3 at strong strength based on one calibrated study reported to show a damaging functional effect consistent with pathogenic control variants.3 This missense change lies within the BRCA2 DNA-binding domain; BayesDel no-AF is 0.454479, above the ENIGMA PP3 threshold of 0.30, SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, and REVEL is 0.842, supporting a damaging protein effect without predicted splice disruption.4
Final classification
VUS
PS3PP3
BRCA2
c.8242G>A
p.Gly2748Ser
This variant
The BRCA2 c.8242G>A (p.Gly2748Ser; G2748S) variant has been reported in ClinVar, where the current expert-panel overall classification is uncertain significance, while multiple clinical laboratory submissions classify it as likely pathogenic or pathogenic.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules; ACMG/AMP 2015 with ENIGMA adaptations).
Classification rationale
PS3PP3
VUS
BRCA2 c.8242G>A
PS3 + PP3
→
VUS
3
vcep_specifications_table9_v1_2_2024_11_18
4
cspec ↗bayesdelspliceai ↗revel
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In the ENIGMA BRCA2 functional evidence table, this exact variant, c.8242G>A (p.Gly2748Ser), is assigned PS3 at strong strength based on one calibrated functional study reported to show a damaging effect consistent with pathogenic control variants.
Specifications Table 9 lists BRCA2 c.8242G>A p.(Gly2748Ser) as PS3 Strong.Table 9 summary states one calibrated study showed a damaging functional effect.
PP3
supporting
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional region used by the ENIGMA bioinformatic framework. BayesDel no-AF is 0.454479, which is above the ENIGMA PP3 threshold of 0.30, SpliceAI shows no significant splice effect with a maximum delta score of 0.06, and REVEL is 0.842; together these findings support a damaging protein effect and meet PP3 at supporting strength.
Protein position 2748 lies within the BRCA2 DNA-binding domain aa 2481-3186.BayesDel no-AF 0.454479 >= 0.30.SpliceAI max delta 0.06.
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PVS1
This missense variant is not a nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, or deletion event, and no RNA-only evidence was identified to support a null-effect mechanism.
PS1
No validated same-amino-acid pathogenic or likely pathogenic comparator was identified in the reviewed materials, so PS1 was not assessed from the currently available evidence.
PS4
No case-control study or quantitative enrichment analysis for this exact variant was identified in the reviewed materials.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic or likely pathogenic variant in an individual with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation analysis or family-based likelihood ratio meeting ENIGMA thresholds was identified for this variant.
PP4
No exact-variant clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified.
Benign
BA1
The population data are well below the ENIGMA BA1 threshold.
BS1
The population frequency does not reach the ENIGMA BS1 thresholds.
BS2
No qualifying observations in adults without BRCA2-related Fanconi anemia features were identified to score BS2 under the ENIGMA point-based framework.
BS3
Available functional evidence does not support a benign effect.
BS4
No quantitative lack-of-segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified for this variant.
BP1
This missense variant does not meet BP1 because it lies within the BRCA2 DNA-binding domain, which is a clinically important functional region in the ENIGMA framework.
BP4
BP4 is not met.
BP5
No exact-variant clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified.
N/A · 11
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71732e-06; MAF= 0.00037%, 6/1614064 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33267e-05; MAF= 0.00333%, 2/60012 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.20448e-05; MAF= 0.00120%, 3/249070 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.78469e-05; MAF= 0.00578%, 2/34574 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,614,064
0 hom · FAF 0.00055%
0 hom · FAF 0.00055%
Admixed American 2 / 60,012 |
0.0033% |
European (non-Finnish) 4 / 1,180,012 |
0.00034% |
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 249,070
0 hom · FAF 0.00096%
0 hom · FAF 0.00096%
Admixed American 2 / 34,574 |
0.0058% |
European (Finnish) 1 / 21,634 |
0.0046% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (7 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 409429)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.842. BayesDel score = 0.454479.
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 · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.
PMID 33609447
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
35736817 ↗
Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.
ONCOKB
17924331 ↗
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.
CLINVAR
18451181 ↗
Functional assays for classification of BRCA2 variants of uncertain significance.
CLINVAR
21671020 ↗
Effect of the overexpression of BRCA2 unclassified missense variants on spontaneous homologous recombination in human cells.
CLINVAR
23108138 ↗
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
CLINVAR
23328489 ↗
Effect of the expression of BRCA2 on spontaneous homologous recombination and DNA damage-induced nuclear foci in Saccharomyces cerevisiae.
CLINVAR
25146914 ↗
An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR