MSH3 c.1269A>G, p.Pro423=
NM_002439.5:c.1269A>G
Likely Benign
This synonymous MSH3 c.1269A>G variant is absent from population databases (PM2), computational tools predict no impact on splicing or function (BP4), it has been reported as likely benign by a reputable source (BP6), and is a silent change without splicing effect (BP7), supporting a final classification of Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
MSH3
Transcript
NM_002439.5
MANE Select
Total Exons
24
Strand
Forward (+)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_002439.2 | Alternative | 24 exons | Forward |
| NM_002439.4 | Alternative | 24 exons | Forward |
| NM_002439.3 | Alternative | 24 exons | Forward |
Variant Details
HGVS Notation
NM_002439.5:c.1269A>G
Protein Change
P423=
Location
Exon 8
(Exon 8 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_002439.5
Genome Browser
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HGVS InputNM_002439:c.1269A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -1.44
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows it is a synonymous change (P423=) with no predicted disruption of splicing or protein truncation. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows no information on de novo status or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows no functional studies performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows no case–control or cohort data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows it is a synonymous change outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, PM2: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows it is not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows no phasing or trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows a synonymous substitution with no length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows no de novo assumption. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows in silico predictors (CADD -1.44, SpliceAI 0.01) do not predict deleterious impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows only benign reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1: "Allele frequency is too high for the disorder". The evidence for this variant shows a frequency of 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows no elevated frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows no data on healthy carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4: "Lack of segregation in affected family members". The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows a single-nucleotide synonym. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows CADD score -1.44 and SpliceAI 0.01 predicting no impact. Therefore, this criterion is applied at Supporting strength because computational predictions indicate no deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows no case reports with alternate etiology. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows a ClinVar entry as Likely Benign from one clinical laboratory with no primary data. Therefore, this criterion is applied at Supporting strength because a reputable source reports it as benign.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, BP7: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows SpliceAI predicts no splicing impact (score 0.01). Therefore, this criterion is applied at Supporting strength because it is a silent change without splicing effect.