The BRCA2 c.7970A>C (p.Lys2657Thr, K2657T) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance and other submitters reported likely pathogenic and uncertain significance assertions.1 This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1614028 alleles overall; highest observed frequency 1/59996 in Admixed American individuals), supporting rarity but not complete absence from population databases.2 In a calibrated BRCA2 functional study summarized by the ENIGMA BRCA1/2 specification, p.Lys2657Thr showed protein function similar to pathogenic control variants, supporting PS3 at strong strength.3 Computational evidence predicts no significant splice impact (SpliceAI max delta score 0.01), while the missense prediction profile is mixed under ENIGMA thresholds (REVEL 0.799; BayesDel 0.270216), so PP3 and BP4 are not independently met.4 A BRCA2 clinical-history likelihood ratio of 1.188967663938105 from 1 proband falls in the ENIGMA neutral zone (>0.48 and <2.08), so neither PP4 nor BP5 is supported by the reviewed multifactorial clinical-history data.5
Final classification
Uncertain Significance
PS3
BRCA2
c.7970A>C
p.Lys2657Thr
This variant
The BRCA2 c.7970A>C (p.Lys2657Thr, K2657T) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance and other submitters reported likely pathogenic and uncertain significance assertions.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 final-classification framework
Classification rationale
PS3
Uncertain Significance
BRCA2 c.7970A>C
PS3
→
Uncertain Significance
3
cspec ↗vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗
4
cspec ↗spliceai ↗revelbayesdel
5
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
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 · 1 applied · 16 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
In a calibrated BRCA2 functional study summarized in ENIGMA Table 9, c.7970A>C (p.(Lys2657Thr)) showed protein function similar to pathogenic control variants, supporting a damaging effect on protein function. This meets PS3 at strong strength.
ENIGMA Table 9 row for c.7970A>C classified as PS3 StrongRichardson 2021 functional evidence
Assessed · not applied
· 10 not met · 6 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.(Lys2657Thr), rather than a nonsense, frameshift, initiation-loss, exon-deletion, or canonical +/-1,2 splice variant.
PS1
No previously classified pathogenic or likely pathogenic variant encoding the same amino acid change was identified in the reviewed sources, so PS1 was not established.
PS4
No case-control study or exact-variant enrichment statistic meeting ENIGMA PS4 requirements was identified for this variant.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,614,028 alleles overall, with highest observed frequency 1/59,996 in the Admixed American population.
PM3
No evidence was identified that this variant was observed in trans with another pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia features, so PM3 could not be assessed.
PP1
No quantitative co-segregation analysis or segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified for this variant.
PP3
This missense variant lies within the BRCA2 DNA-binding domain, but ENIGMA PP3 for missense variants in this region requires BayesDel no-AF >=0.30 or predicted splice impact with SpliceAI >=0.2.
PP4
The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband.
Benign
BA1
Available population data do not meet the ENIGMA BA1 threshold.
BS1
Available population data do not meet ENIGMA BS1 thresholds.
BS2
No qualifying co-occurrence or unaffected-adult evidence meeting the ENIGMA BS2 point system was identified for this variant.
BS3
Available calibrated functional evidence supports a damaging effect rather than a neutral effect for this variant.
BS4
No quantitative lack-of-segregation analysis or segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified for this variant.
BP1
This missense variant is located within the BRCA2 DNA-binding domain (aa 2481-3186).
BP4
This missense variant is within the BRCA2 DNA-binding domain, and SpliceAI predicts no significant splice impact (max delta score 0.01).
BP5
The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband.
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= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66678e-05; MAF= 0.00167%, 1/59996 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,028
0 hom
0 hom
Admixed American 1 / 59,996 |
0.0017% |
+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.799. BayesDel score = 0.270216.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.
Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-bindin
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links