Variant classification summary

NM_000059.4:c.6748A>G

BRCA2 · NP_000050.3:p.(Thr2250Ala) · NM_000059.4

GRCh37: chr13:32915240 A>G · GRCh38: chr13:32341103 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BS1 strong benign BP1 strong benign BP5 strong benign BP6 supporting benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Thr2250Ala)

gnomAD AF

0.0001084269419265299 (v4.1)

ClinVar

Benign

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): gnomAD v2.1 non-cancer grpmax FAF 0.00010864 exceeds the 0.01% threshold.

2

BP1 (Strong): missense at residue 2250 lies outside the clinically important functional domains, with SpliceAI max delta 0.016 (<=0.1).

3

BP5 (Strong): multifactorial odds >100:1 in favor of neutrality (LR<0.01) meet the <=0.05 threshold.

4

BP6 (Supporting): the ENIGMA expert panel classified this variant as Benign.

5

Overall: Benign, per the ENIGMA BRCA2 v1.2 rule requiring at least two Strong benign criteria.

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, the three met Strong benign criteria (BS1, BP1, and BP5) satisfy the Benign rule requiring at least two Strong benign criteria.

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	Not met: c.6748A>G is a missense change (p.Thr2250Ala), not a null or canonical splice-site variant.	cspec
PS1	Not met	Not met: no pathogenic or likely pathogenic variant producing the same amino-acid change at residue 2250 was reported.	cspec PMID:16683254 PMID:23683081 PMID:24323938
PS2	N/A	Not applicable: the ENIGMA BRCA2 specification designates PS2 as not applicable, so no de novo evidence was adjudicated.	cspec
PS3	Not assessed	Not assessed: the variant is not in the ENIGMA calibrated functional-assay table, and no qualifying assay result was available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:24323938
PS4	Not assessed	Not assessed: no ethnicity- and country-matched case-control study meeting ENIGMA thresholds was identified.	cspec
PM1	N/A	Not applicable: the ENIGMA BRCA2 specification designates PM1 as not applicable, and residue 2250 is outside the specified functional domains.	cspec vcep_appendices_v1_2_2024_11_18 PMID:17924331
PM2	Not met	Not met: the variant is present in population controls (gnomAD v2.1 28/251,358 and v4.1 175/1,613,990 alleles), where absence is required.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband with a Fanconi anemia phenotype or second BRCA2 pathogenic variant was documented.	cspec
PM4	N/A	Not applicable: the ENIGMA BRCA2 specification does not use PM4, and this missense change does not alter protein length.	cspec
PM5	N/A	Not applicable: PM5 applies only to protein-termination-codon variants, and c.6748A>G is a missense change.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA BRCA2 specification designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no quantitative co-segregation data (likelihood ratio, meiosis count, affected-relative genotypes) were available.	cspec PMID:23683081
PP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates PP2 as not applicable.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.016 is below the >=0.20 PP3 splicing threshold.	cspec spliceai
PP4	Not met	Not met: the multifactorial clinical evidence favors neutrality, not the pathogenicity PP4 requires.	cspec PMID:23683081
PP5	Not met	Not met: the ClinVar expert-panel assertion is Benign, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v2.1 grpmax FAF 0.00010864 (0.0109%) is below the 0.1% BA1 threshold.	cspec gnomad_v2
BS1	Met	Met (Strong): gnomAD v2.1 non-cancer grpmax FAF 0.00010864 exceeds the 0.01% BS1 Strong threshold.	cspec gnomad_v2
BS2	Not assessed	Not assessed: no adequately documented Fanconi anemia phenotype assessment or Table 8 point data were available.	cspec
BS3	Not assessed	Not assessed: no ENIGMA-calibrated benign functional assay result for this variant was available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:24323938
BS4	Not assessed	Not assessed: no quantitative segregation data (affected non-carriers, likelihood ratio) were available.	cspec PMID:23683081
BP1	Met	Met (Strong): missense at residue 2250 lies outside the clinically important domains, with SpliceAI max delta 0.016 (<=0.1).	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: BP3 applies only to in-frame indels in repetitive regions; this is a missense change.	cspec
BP4	N/A	Not applicable: BP4's missense path requires the variant to lie inside a specified functional domain; residue 2250 is outside.	cspec spliceai bayesdel
BP5	Met	Met (Strong): multifactorial odds >100:1 in favor of neutrality (LR<0.01) meet the <=0.05 BP5 Strong threshold.	cspec PMID:23683081
BP6	Met	Met (Supporting): the ENIGMA expert panel classified this variant as Benign.	clinvar
BP7	Not assessed	Not assessed: BP7 sequence-based paths apply only to silent or intronic variants, and no mRNA-only assay result was available.	cspec

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.