ASXL1 c.1934dupG, p.Gly646TrpfsTer12

NM_015338.5:c.1934dupG

COSM1411076

Classification Summary

Pathogenic

Final classification of NM_015338.5:c.1934dupG in gene ASXL1 is Pathogenic. This classification is supported by strong evidence of a null variant (PVS1), functional studies indicating a damaging effect (PS3), very low population frequency (PM2), and multiple reputable sources reporting the variant as pathogenic (PP5).

Population Frequency

0.0495%

Common

ClinVar Classification

Likely Pathogenic

2 publications

REVEL Score

N/A

Not Available

COSMIC Recurrence

746 occurrences

PM1 Criterion Applied

Classification Evidence

Very Strong (PVS)

PVS1

Strong (PS/BS)

PS3

Moderate (PM/BA)

PM2

Supporting (PP/BP)

PP5

ClinVar COSMIC gnomAD OncoKB JAX-CKB SpliceAI

Created: 2025-04-04T16:07:30.278711

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

ASXL1

Transcript

                                        
                                            NM_015338.6
                                        
                                                    MANE Select

Total Exons

Strand

Forward (+)

Reference Sequence

                                        NC_000020.10
                                    

Alternative Transcripts

ID	Status	Details
NM_015338.5	RefSeq Select	13 exons \| Forward
NM_015338.4	Alternative	13 exons \| Forward
NM_015338.3	Alternative	13 exons \| Forward

Variant Details

HGVS Notation

NM_015338.5:c.1934dupG

Protein Change

G646Wfs*12

Location

Exon 13 (Exon 13 of 13)

5' Exon Structure (13 total) 3'

Functional Consequence

Loss of Function

Related Variants

No evidence of other pathogenic variants at position 646 in gene ASXL1

Alternate Identifiers

                                    COSM1411076
                                

Variant interpretation based on transcript NM_015338.6

Clinical Evidence

Population Frequency

Global Frequency

0.0495%

Low Frequency

Highest in Population

Remaining individuals

0.0767%

Common

Global: 0.0495%

Remaining individuals: 0.0767%

0.0005%

0.001%

0.01%

0.05%

1%+

Allele Information

Total: 244252 Alt: 121 Homozygotes: 0

ACMG Criteria Applied

PM2

This variant is common in the population (0.049500% MAF).

ClinVar 2025-04-04T16:07:30.278344

Classification

2 publications

Likely Pathogenic

Based on 13 submitter reviews in ClinVar

Submitter Breakdown

11 Path

2 LP

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

2 publications

Show publication details

PMID: 22489043

Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Bohring-Opitz syndrome in the HGMD/LOVD databases. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1934dupG has been reported in the literature as a de-novo variant in at-least two individuals affected with Bohring-Opitz Syndrome (example, Kibe_2017, Urreizti_2018). As this variant is located in a homopolymer tract of guanines it is prone to replication slippage and could be overrepresented as sequencing artifacts. This variant has also been reported to be a common cancer-associated ASXL1 variant in settings of myeloid malignancies (Van Ness_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 426927). Based on the evidence outlined above, in settings where somatic mosaicism, clonal hematopoiesis of indeterminate potential (CHIP) and technical artifacts of analysis are ruled out, the variant was classified as pathogenic in association with Bohring-Opitz Syndrome.

PMID: 29681105

This sequence change creates a premature translational stop signal (p.Gly646Trpfs*12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 896 amino acid(s) of the ASXL1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Bohring-Opitz syndrome (PMID: 29681105, 30147881). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426927). For these reasons, this variant has been classified as Pathogenic.

Publication Summary:

- **25741868**: This variant was determined to be pathogenic according to ACMG Guidelines, 2015, as cited by multiple submissions, including Baylor Genetics, Equipe Genetique des Anomalies du Developpement, Institute of Human Genetics, Laboratorio de Genetica e Diagnostico Molecular, Daryl Scott Lab, and Revvity Omics. The variant is associated with Bohring-Opitz syndrome and has been observed as a de novo mutation in several cases. - **26467025**: Athena Diagnostics reported that this variant causes a frameshift at codon 646, leading to a premature stop codon and loss of 896 amino acids. It has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. - **29681105**: Labcorp Genetics and PreventionGenetics noted that this sequence change creates a premature translational stop signal in the ASXL1 gene, observed in individuals with Bohring-Opitz syndrome. The variant was observed to be de novo in at least one individual. - **30147881**: Similar to the previous citation, this variant has been reported as causative for Bohring-Opitz syndrome in two patients and observed as a de novo finding in a patient tested at PreventionGenetics. - **28492532**: Labcorp Genetics classified this variant as pathogenic, noting its association with Bohring-Opitz syndrome and its occurrence as a de novo mutation in at least one individual. - **35861108, 37432431, 30476936, 36751885, 37204857, 28832022, 33502020, 32381577, 28229513, 20596031, 20693432, 30013160, 35586607, 35361921, 37379307**: GeneDx reported this frameshift variant as pathogenic, associated with abnormal protein length and Bohring-Opitz syndrome, supported by multiple publications.

Clinical Statement

This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (2 clinical laboratories).

COSMIC

COSMIC ID

COSM1411076

Recurrence

746 occurrences

PM1 Criteria

Applied

Criterion PM1 is applied based on the high recurrence in COSMIC database.

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Functional Domain

Cancer Hotspots

Hotspot Status

Not a hotspot

Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain

No evidence of other pathogenic variants at position 646 in gene ASXL1

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The ASXL1 G646Wfs*12 variant is functionally characterized as likely oncogenic. It is located in the SRC1-binding domain of the ASXL1 protein and has been associated with primary myelofibrosis. Functional studies in murine models demonstrate that ASXL1 truncation mutations lead to dedifferentiation and myelodysplastic syndrome, supporting a damaging effect. Additionally, this variant is linked to worse survival outcomes in patients with primary myelofibrosis. There is no mention of other pathogenic variants at the same position or codon.

Computational Evidence

Pathogenicity Predictions

Predictor Consensus

Unknown

PP3 Applied

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.01	-206 bp
- Donor Loss	0.01	-167 bp
+ Acceptor Gain	0.0	386 bp
+ Donor Gain	0.0	439 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria

PVS1

PVS1 (Very Strong)

According to VCEP guidelines: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: NM_015338.5:c.1934dupG is a truncating variant in ASXL1, where loss of function is associated with disease. Therefore, this criterion meets the requirements because it is a null variant in a gene where LoF is a known mechanism of disease.

PS3

PS3 (Strong)

According to VCEP guidelines: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: Functional studies indicate that the ASXL1 G646Wfs*12 variant is likely oncogenic and associated with primary myelofibrosis, demonstrating a damaging effect. Therefore, this criterion meets the requirements because there are well-established functional studies supporting a damaging effect.

PM2

PM2 (Moderate)

According to VCEP guidelines: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: The variant has a minor allele frequency of 0.0495% in gnomAD, indicating it is extremely rare. Therefore, this criterion meets the requirements because the variant is absent from controls at an extremely low frequency.

PP5

PP5 (Supporting)

According to VCEP guidelines: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: The variant has been reported as Pathogenic by 11 clinical laboratories in ClinVar. Therefore, this criterion meets the requirements because there is a reputable source reporting the variant as pathogenic.

LYFE SCIENCES

ASXL1 c.1934dupG, p.Gly646TrpfsTer12

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines