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ETV6
Final classification
Benign
BA1BP7
ETV6
c.642G>A
p.Pro214=
synonymous · exon 5
Gene context NCBI Gene ↗ OncoKB ↗

ETV6 encodes an ETS-family transcription factor that is essential for hematopoiesis and for maintenance of the developing vascular network. It contains an N-terminal pointed (PNT) domain for protein-protein interactions and a C-terminal DNA-binding domain. ETV6 acts as a tumor suppressor: its rearrangements are among the most common alterations in hematologic malignancies and are also linked to congenital fibrosarcoma, while germline mutations predispose to blood cancers such as acute lymphoblastic leukemia. It can also promote tumorigenesis through fusions that alter the activity of partner genes or nearby proto-oncogenes.

This variant

ETV6 is a tumor suppressor whose germline mutations predispose to hematologic malignancies such as acute lymphoblastic leukemia, so establishing that a variant is benign matters clinically. This synonymous variant (p.(Pro214=)) is classified Benign: it leaves the ETV6 protein unchanged, shows no predicted splicing disruption, and is too common in the general population (2.13% African/African American allele frequency) to be a leukemia-predisposing mutation.

Transcript
NM_001987.4
HGVS · transcript:coding
NM_001987.4:c.642G>A
GRCh38
chr12:11869602 G>A
GRCh37
chr12:12022536 G>A
Basis Benign: no ETV6 VCEP exists, so generic ACMG/AMP 2015 rules apply; BA1 met at stand-alone (gnomAD v4.1 AF 2.13033% > 1% threshold) and BP7 supporting (SpliceAI max delta 0.003). ▾
Benign: no ETV6 VCEP exists, so generic ACMG/AMP 2015 rules apply; BA1 met at stand-alone (gnomAD v4.1 AF 2.13033% > 1% threshold) and BP7 supporting (SpliceAI max delta 0.003).
Classification rationale
BA1BP7 Benign
ETV6 c.642G>A synonymous · exon 5

BA1 (Stand-alone Benign): gnomAD v4.1 African/African American allele frequency 2.13033% (1598/75012 alleles, 21 homozygotes) exceeds the 1% BA1 threshold. BP7 (Supporting): synonymous variant (p.(Pro214=)) with no predicted splice impact (SpliceAI max delta 0.003). Overall classification: Benign — BA1 at stand-alone strength under generic ACMG/AMP 2015 combination rules (no ETV6 VCEP available), with no pathogenic-direction criteria met.

BA1 + BP7 → Benign
Gene diagram · NM_001987.4 · variants mapped to exon structure
ETV6 NM_001987.4
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
✓
BA1 stand-alone Benign
Met (stand-alone benign): gnomAD v4.1 African/African American allele frequency 2.13033% (1598/75012 alleles) exceeds the 1% BA1 threshold.
No ETV6 ClinGen VCEP specification was retrieved; generic ACMG/AMP population-frequency operating thresholds apply.gnomAD v4.1: African/African American AF 0.0213033 (1598/75012), 21 homozygotes, and grpmax FAF 0.0204335.The independent gnomAD v2.1 dataset is concordant: African/African American AF 0.0216363 (540/24958), 10 homozygotes, and grpmax FAF 0.0207937.
gnomad_v4 ↗gnomad_v2 ↗
✓
BP7 supporting Benign
Met (supporting): synonymous variant with SpliceAI max delta 0.003, indicating no predicted splice impact.
SpliceAI Lookup (source_registry key 'spliceai') for NM_001987.4:c.642G>A: max delta score = 0.003, described as 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00)' (evidence_brief.json spliceai.sentence); no acceptor/donor gain or loss scores were flagged as significant.Variant is synonymous at the protein level: NP_001978.1:p.(Pro214=) / p.(P214=) per case_summary.json normalization, confirming BP7 (silent variant) applicability rather than a missense change.
spliceai ↗
Assessed · not applied · 1 not met · 14 not assessed
Pathogenic
PS2 Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.
PS3 Not assessed: no validated functional assay for this variant was available; SpliceAI (max delta 0.00) is only a computational prediction.
PS4 Not assessed: no variant-specific case-control or statistical enrichment data were available.
PM2 Not met: gnomAD v4.1 African/African American allele frequency 2.13033% shows the variant is far too common for PM2 rarity.
PM3 Not assessed: no affected-proband data pair this variant with a pathogenic ETV6 variant in trans.
PM6 Not assessed: no parental genotypes or de novo testing result was provided.
PP1 Not assessed: no pedigree, relative genotypes, or informative meioses were provided for segregation analysis.
PP4 Not assessed: no proband phenotype or testing indication was supplied to assess a specific ETV6-associated phenotype.
PP5 Not assessed: no ClinVar expert-panel pathogenic assertion exists for this exact variant.
Benign
BS2 Not assessed: population datasets lack phenotype, age, and disease-status data for individual carriers.
BS3 Not assessed: no validated functional assay of this variant was found; SpliceAI max delta 0.00 is computational only.
BS4 Not assessed: no family data show lack of segregation between this variant and a relevant phenotype.
BP2 Not assessed: no co-occurrence or phase observation was available.
BP5 Not assessed: no evidence of an alternate molecular diagnosis explaining the reported phenotype was available.
BP6 Not assessed: no ClinVar expert-panel benign assertion exists for this exact variant.
N/A · 11 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BS1 · BP1 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.0011889; MAF= 0.11889%, 1919/1614094 alleles, homozygotes = 22) and has highest observed frequency in the African/African American population (AF= 0.0213033; MAF= 2.13033%, 1598/75012 alleles, homozygotes = 21); grpmax FAF= 0.0204335.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00215037; MAF= 0.21504%, 608/282742 alleles, homozygotes = 10) and has highest observed frequency in the African/African American population (AF= 0.0216363; MAF= 2.16363%, 540/24958 alleles, homozygotes = 10); grpmax FAF= 0.0207937.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0017376194613379669, 32/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.12% · 1919 / 1,614,094
22 hom · FAF 2%
African/African American
1598 / 75,012
2.1%
21 hom
Admixed American
99 / 60,012
0.16%
Remaining individuals
91 / 62,508
0.15%
Middle Eastern
6 / 6,060
0.099%
South Asian
11 / 91,076
0.012%
1 hom
European (non-Finnish)
114 / 1,180,014
0.0097%
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.22% · 608 / 282,742
10 hom · FAF 2.1%
African/African American
540 / 24,958
2.2%
10 hom
Remaining individuals
10 / 7,224
0.14%
Admixed American
42 / 35,436
0.12%
European (non-Finnish)
14 / 129,094
0.011%
South Asian
2 / 30,616
0.0065%
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.17% · 32 / 18,416
0 hom · FAF 1.7%
African/African American
25 / 1,020
2.5%
Latino/Admixed American
2 / 838
0.24%
Remaining individuals
2 / 1,138
0.18%
East Asian
1 / 1,338
0.075%
European (non-Finnish)
2 / 11,736
0.017%
+ 4 not observed (Ashkenazi Jewish, European (Finnish), Middle Eastern, South Asian)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 1336291)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗ 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. CLINVAR
31275557 ↗ Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. CLINVAR
24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency. CLINVAR
22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR
23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR
24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR