NM_000059.3:c.7970A>C

BRCA2 · NP_000050.2:p.(Lys2657Thr) · NM_000059.3

GRCh37: chr13:32936824 A>C · GRCh38: chr13:32362687 A>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Lys2657Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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.

Final determination: A single strong pathogenic criterion without additional qualifying pathogenic or benign criteria does not meet ENIGMA Table 3 thresholds for likely pathogenic, pathogenic, likely benign, or benign classification and is therefore classified as uncertain significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	This variant is a missense substitution, p.(Lys2657Thr), rather than a nonsense, frameshift, initiation-loss, exon-deletion, or canonical +/-1,2 splice variant. SpliceAI predicts no significant splice impact (max delta score 0.01), so available evidence does not support a loss-of-function mechanism for PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	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.	cspec clinvar
PS2	N/A	This criterion is not calibrated for BRCA1/2-related cancers in the ENIGMA BRCA2 specification.	cspec
PS3	Met	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.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
PS4	Not assessed	No case-control study or exact-variant enrichment statistic meeting ENIGMA PS4 requirements was identified for this variant. The reviewed ENIGMA posterior probability and multifactorial tables did not provide an exact-variant PS4 result.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not used as an independent criterion in the ENIGMA BRCA2 specification because domain information is incorporated into the BRCA2 bioinformatic framework.	cspec
PM2	Not met	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. ENIGMA PM2_Supporting requires absence from population controls, so available data do not show complete absence.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	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.	cspec
PM4	N/A	PM4 is not applicable because this is a missense substitution and the ENIGMA BRCA2 specification does not use PM4 for this context.	cspec
PM5	N/A	In the ENIGMA BRCA2 specification, PM5 is adapted for protein-truncating variants and is not used here for this missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not calibrated for BRCA1/2-related cancers in the ENIGMA BRCA2 specification.	cspec
PP1	Not assessed	No quantitative co-segregation analysis or segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified for this variant.	cspec
PP2	N/A	PP2 is not used for BRCA2 in the ENIGMA specification because benign missense variation is too common for this code to be informative.	cspec
PP3	Not met	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. The observed BayesDel score is 0.270216 and SpliceAI max delta score is 0.01; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for PP3. Therefore PP3 is not met.	cspec bayesdel spliceai revel
PP4	Not met	The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband. This is below the ENIGMA PP4 supporting threshold of 2.08, so available multifactorial clinical-history evidence does not support PP4.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Not met	Available population data do not meet the ENIGMA BA1 threshold. The variant is absent from gnomAD v2.1 and has total allele frequency 6.195679381026847e-07 in gnomAD v4.1, far below the BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Available population data do not meet ENIGMA BS1 thresholds. The highest observed population allele frequency is 1.666777785185679e-05 in Admixed American individuals, which is below the BS1 supporting threshold of 0.00002 and below the strong threshold of 0.0001.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No qualifying co-occurrence or unaffected-adult evidence meeting the ENIGMA BS2 point system was identified for this variant.	cspec
BS3	Not met	Available calibrated functional evidence supports a damaging effect rather than a neutral effect for this variant. Therefore BS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
BS4	Not assessed	No quantitative lack-of-segregation analysis or segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified for this variant.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Not met	This missense variant is located within the BRCA2 DNA-binding domain (aa 2481-3186). Although SpliceAI predicts no significant splice impact (max delta score 0.01), ENIGMA BP1_Strong requires a missense or silent variant outside a clinically important functional domain, so BP1 is not met.	cspec spliceai
BP2	N/A	BP2 is not used independently in the ENIGMA BRCA2 framework and is only considered within the BS2 context.	cspec
BP3	N/A	BP3 is not applicable in the ENIGMA BRCA2 specification.	cspec
BP4	Not met	This missense variant is within the BRCA2 DNA-binding domain, and SpliceAI predicts no significant splice impact (max delta score 0.01). However, ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF <=0.18, and the observed BayesDel score is 0.270216; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for BP4. Therefore BP4 is not met.	cspec bayesdel spliceai revel
BP5	Not met	The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband. This is above the BP5 supporting threshold of 0.48 and falls within the ENIGMA neutral zone (>0.48 and <2.08), so BP5 is not met.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
BP7	N/A	This is a missense variant within a clinically important functional domain, and no RNA-only benign assay result was identified. Although SpliceAI predicts no significant splice impact (max delta score 0.01), BP7 is not applicable in this context.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.