APC c.5271T>C, p.Ser1757=
NM_001127510.3:c.5271T>C
Likely Benign
This synonymous APC variant shows no impact on splicing by in silico prediction, lacks functional or segregation evidence, and has a Popmax AF (0.0229%) meeting BS1_Strong. Combined with BP4 and BP6, the evidence supports a Likely Benign classification.
ACMG/AMP Criteria Applied
BS1
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
APC
Transcript
NM_001127510.1
Total Exons
17
Strand
Forward (+)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001127510.3 | Alternative | 17 exons | Forward |
| NM_001127510.2 | Alternative | 17 exons | Forward |
Variant Details
HGVS Notation
NM_001127510.3:c.5271T>C
Protein Change
S1757=
Location
Exon 17
(Exon 17 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001127510.1
Genome Browser
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HGVS InputNM_001127510:c.5271T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00319%
Rare
Highest in Population
South Asian
0.0229%
Low Frequency
Global: 0.00319%
South Asian: 0.0229%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250490Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00319%, 8/250490 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.0229%, 7/30612 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
8 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (3 clinical laboratories) and 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: -0.41
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants in a gene where LOF is a known mechanism. This variant is synonymous (S1757=) and does not create a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. This variant is synonymous and does not change the amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to de novo occurrences with confirmed parental relationships. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires functional assays demonstrating a damaging effect. No functional studies are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when there is statistical evidence of increased prevalence in affected individuals. No case–control or phenotype data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in mutational hotspots or critical domains. S1757= is outside known functional or mutational hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2_Supporting requires allele frequency ≤0.0003% if AC>1. The gnomAD Popmax AF is 0.0229% (>0.0003%). Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG, PM3 applies to recessive disease genes when variants are observed in trans with a pathogenic variant. No such data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG, PM4 applies to protein length changes. This variant is synonymous and does not alter length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at amino acid positions with a known LP/P variant. This is a silent change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to presumed de novo occurrences without confirmation. No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies when there is segregation in families. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG, PP2 applies to missense variants in genes with low benign missense variation. This variant is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to non-canonical splicing or missense variants with deleterious in silico predictions. SpliceAI predicts no effect and no damaging missense change exists. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG, PP4 applies if patient phenotype is highly specific and variant fits. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG, PP5 applies when a reputable source reports pathogenic. ClinVar reports benign/likely benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires AF ≥0.1% (0.001). The highest Popmax AF is 0.0229% (0.000229), below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, BS1_Strong: "GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.001% (0.00001)". The South Asian Popmax AF is 0.0229% (0.000229), which exceeds the threshold. Therefore, BS1 is applied at Strong strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies with observations in healthy individuals. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires RNA assays demonstrating no aberration. No functional RNA assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to non-segregation in affected members. No family data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants outside defined domains. This variant is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies when observed in trans with a pathogenic variant. No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG, BP3 applies to in-frame indels in repetitive regions. This is a single-nucleotide silent change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4_Supporting: "Synonymous (silent) or intronic variants: multiple in silico splicing predictors suggest no impact". SpliceAI predicts no impact on splicing. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG, BP5 applies when an alternate genetic basis explains the phenotype. No alternate basis is documented. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG, BP6: "Reputable source recently reports variant as benign but evidence not available for independent evaluation". ClinVar lists this variant as Likely benign/Benign. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG, BP7 requires a synonymous variant ≥7 bp from splice sites with multiple in silico predictors suggesting no impact. Distance from splice junction is not documented and only one predictor (SpliceAI) is reported. Therefore, BP7 is not applied.