Variant classification summary

NM_022552.4:c.2116G>C

DNMT3A · NP_072046.2:p.(Gly706Arg) · NM_022552.4

GRCh37: chr2:25463566 C>G · GRCh38: chr2:25240697 C>G

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PM2_Moderate PP3_Supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Gly706Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The DNMT3A c.2116G>C (p.Gly706Arg; p.G706R) variant has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.

3

OncoKB classifies this variant as Likely Oncogenic with a likely loss-of-function biological effect, but the available evidence does not provide a well-established variant-specific functional study result sufficient for ACMG PS3 or BS3.

4

Computational evidence supports a deleterious protein effect, with REVEL 0.971, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	N/A	This is a missense variant, p.(Gly706Arg), and it does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice variants. Although loss of function is a supported disease mechanism for DNMT3A, the available PVS1 framework does not support applying PVS1 to this variant type.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant.
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified.
PS3	Not met	Available evidence cites functional literature and OncoKB describes this variant as likely oncogenic with a likely loss-of-function effect, but no well-established functional study result for this specific variant was identified that is sufficient to apply ACMG PS3.	oncokb PMID:27359055 PMID:34429321
PS4	Not met	No enrichment of this variant in affected individuals compared with controls was identified. This variant has not been reported in ClinVar, and no qualifying case-control or case-series evidence was identified.	clinvar
PM1	Not met	Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and the reviewed literature did not establish PM1-level domain evidence for this specific variant.	hotspots PMID:27359055 PMID:34429321
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 threshold of 0.1% for non-VCEP review and supports rarity in the general population.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence indicates a recessive disease context or a trans occurrence with another pathogenic variant for this DNMT3A variant.
PM4	N/A	This variant is a missense substitution and does not produce a protein length change, so PM4 is not applicable.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at codon 706 that would support PM5.
PM6	Not assessed	No assumed de novo occurrence was identified.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	Gene-level missense constraint or a low rate of benign missense variation sufficient for PP2 was not established in the available evidence.
PP3	Met	Computational evidence supports a deleterious effect for this missense variant. REVEL is 0.971, which is strongly damaging in silico, while SpliceAI shows no meaningful splice effect with a max delta score of 0.04, supporting a protein-altering rather than splice-altering mechanism.	spliceai
PP4	Not assessed	No phenotype or family history information was provided that is sufficiently specific to DNMT3A-related disease to support PP4.
PP5	Not met	No reputable germline database classification supporting pathogenicity was identified because this variant is absent from ClinVar.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign stand-alone threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign strong threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2.
BS3	Not met	Reviewed evidence does not identify well-established functional studies showing normal protein function for this specific variant. OncoKB instead describes the variant as likely oncogenic with likely loss-of-function effect, so BS3 is not supported.	oncokb PMID:34429321
BS4	Not assessed	No segregation data showing lack of cosegregation were identified.
BP1	Not assessed	The available evidence does not establish that missense variation is generally a non-disease mechanism for DNMT3A, so BP1 was not applied.
BP2	Not assessed	No phase information with another pathogenic variant was identified.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable.
BP4	Not met	Available computational evidence does not support a benign effect. REVEL is 0.971, which argues against BP4, and SpliceAI predicts no meaningful splice effect with a max delta score of 0.04.	spliceai
BP5	Not assessed	No alternate molecular explanation for disease was identified.
BP6	Not met	No reputable germline database classification supporting benignity was identified because this variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or intronic change, so BP7 is not applicable.

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.