BP1_Strong is met: c.750G>A is a silent (synonymous) substitution (p.Val250=) located outside both BRCA2 clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1 threshold).1 BS1_Supporting is met: the gnomAD v2.1 non-cancer exome filter allele frequency (FAF) is 4.75e-05 (0.00475%), falling in the ENIGMA BS1_Supporting range (FAF > 0.002% and ≤ 0.01%). The highest population sub-frequency is in European (non-Finnish) at 7.77e-05 (10/128,766 alleles).2 PM2_Supporting is not met because the variant is present in gnomAD population databases (11 alleles in v2.1, 134 alleles in v4.1), failing the ENIGMA requirement of absence from outbred population controls.3 PP3 is not met: SpliceAI max delta is 0.00 (< 0.2) and the variant is outside clinically important functional domains, failing both PP3 application pathways in the ENIGMA specification.4 BA1 (Stand-Alone Benign) is not met: gnomAD grpmax FAF of 4.75e-05 (v2.1) and 9.28e-05 (v4.1) are both well below the 0.1% (FAF > 0.001) threshold.5 BS3, BS4, PP1, PP4, BP5, and BP7 are not assessed due to absence of variant-specific functional, segregation, or clinical-history LR data in the ENIGMA VCEP-curated datasets (Table 9, clinical_history_LR.xlsx, HUMU-40-1557-s001, ST7).6 PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP2, PP5, BP2, BP3, BP6 are not applicable for this synonymous variant under the ENIGMA VCEP framework.7 Under the ENIGMA Table 3 combination rules, 1 Strong Benign criterion (BP1_Strong) plus 1 Supporting Benign criterion (BS1_Supporting) reaches the threshold for Likely Benign. Under the ENIGMA point system: BP1_Strong = -4 points, BS1_Supporting = -1 point, total = -5 points (Likely Benign range: -6 to -2).8 ClinVar lists this variant as Likely Benign with expert panel review status by ENIGMA (ClinVar ID 135814), with 10 clinical laboratories reporting Likely Benign and 5 reporting Benign. This clinical consensus is concordant with the ENIGMA framework-based assessment.9
BRCA2
Final classification
Likely Benign
BRCA2 c.750G>A · p.Val250=
BRCA2
BP1_Strong is met: c.750G>A is a silent (synonymous) substitution (p.Val250=) located outside both BRCA2 clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1 threshold).
ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3 combination rules applied to adjudicated criteria. One Strong Benign criterion (BP1_Strong) plus two Supporting Benign criteria (BS1_Supporting, BP6_Supporting) independently satisfy multiple Likely Benign rules: 1 Strong (Benign) + 1 Supporting (Benign) and 2 Supporting (Benign). No pathogenic criteria are met; no conflicting evidence present. ENIGMA point system (conflicting_evidence only) confirms: BP1_Strong (-4) + BS1_Supporting (-1) + BP6_Supporting (-1) = -6, within Likely Benign range (-6 to -2). ClinVar expert panel (ENIGMA) also reports Likely Benign (ClinVar ID 135814).
Classification rationale
BS1BP1BP6
Likely Benign
BRCA2 c.750G>A
BS1 + BP1 + BP6
→
Likely Benign
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
134 / 1,613,406
0.0083%
Highest · Amish
0.22%
Homozygotes
0
grpmax FAF
0.0093%
Allele frequency by ancestry — gnomAD v4.1
observed in 3 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Amish | 2 / 912 | 0.22% | 0 |
| European (non-Finnish) | 128 / 1,179,546 | 0.011% | 0 |
| African/African American | 2 / 74,900 | 0.0027% | 0 |
| Admixed American | 0 / 59,970 | — | — |
| European (Finnish) | 0 / 64,002 | — | — |
| East Asian | 0 / 44,886 | — | — |
| Middle Eastern | 0 / 6,080 | — | — |
| South Asian | 0 / 91,050 | — | — |
| Ashkenazi Jewish | 0 / 29,600 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 8.30541e-05; MAF= 0.00831%, 134/1613406 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00219298; MAF= 0.21930%, 2/912 alleles, homozygotes = 0); grpmax FAF= 9.279e-05.
Overall AF
11 / 282,244
0.0039%
Highest · European (non-Finnish)
0.0078%
Homozygotes
0
grpmax FAF
0.0047%
Allele frequency by ancestry — gnomAD v2.1
observed in 2 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 10 / 128,766 | 0.0078% | 0 |
| African/African American | 1 / 24,916 | 0.004% | 0 |
| Admixed American | 0 / 35,356 | — | — |
| Ashkenazi Jewish | 0 / 10,360 | — | — |
| East Asian | 0 / 19,944 | — | — |
| European (Finnish) | 0 / 25,098 | — | — |
| Remaining individuals | 0 / 7,216 | — | — |
| South Asian | 0 / 30,588 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 3.89734e-05; MAF= 0.00390%, 11/282244 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76603e-05; MAF= 0.00777%, 10/128766 alleles, homozygotes = 0); grpmax FAF= 4.75e-05.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (5 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 135814)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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 · 5 PMIDs triaged · 4 high-priority
5papers 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.
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
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
27495310 ↗
functional
Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.
Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family
BS3PS3PS4
31843900 ↗
splicing rna
Characterization of splice-altering mutations in inherited predisposition to cancer.
Mutations responsible for inherited disease may act by disrupting normal transcriptional splicing. Such mutations can be difficult to detect, and their effects difficult to characterize, because many lie deep within exons or introns where they may alter splice enhancers or silencers or introduce new splice acceptors or donors. Multiple mutation-specific and genome-wide approaches have been develop
BP7PP3PS3PS4PVS1
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links