NM_015450.3:c.1884A>C

POT1 · NP_056265.2:p.(Thr628=) · NM_015450.3

GRCh37: chr7:124464037 T>G · GRCh38: chr7:124823983 T>G

Gene: POT1 Transcript: NM_015450.3

Final call

Benign

BA1 stand-alone benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

POT1

Transcript

NM_015450.3

Protein

NP_056265.2:p.(Thr628=)

gnomAD AF

0.005899159007833227 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=) in POT1 classified as Benign based on the ACMG/AMP 2015 guidelines.

This variant is present at high frequency in population databases: gnomAD v2.1 reports an allele frequency of 1.07% (2980/279114 alleles, 157 homozygotes), with the highest subpopulation frequency of 11.1% in the African/African American population (grpmax FAF 10.7%); gnomAD v4.1 reports an allele frequency of 0.59% (9370/1588362 alleles, 477 homozygotes), with grpmax FAF of 11.0%. This frequency meets the stand-alone benign criterion BA1.

ClinVar classifies this variant as Benign based on consensus from 7 clinical laboratories (ClinVar variation ID: 475068), providing supporting evidence for a benign classification (BP6).

SpliceAI predicts no impact on splicing (max delta score = 0.00), and the high population frequency indicates the nucleotide is not conserved, satisfying BP7 for this synonymous variant.

No variant-specific functional studies, de novo observations, segregation data, or case-control evidence were identified for this variant. The ClinVar-cited publications (PMID:25741868, PMID:26467025, PMID:28492532) are methodology and guideline papers that do not mention NM_015450.3:c.1884A>C.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=) with no predicted amino acid change; PVS1 applies only to null variants (nonsense, frameshift, canonical splice). The ClinGen SVI PVS1 framework (PMC6185798) confirms this variant does not fall into a null-variant bucket.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires an alternate nucleotide change at the same position with an established pathogenic classification. This synonymous variant has no known pathogenic missense comparator at c.1884.
PS2	Not met	No de novo observation data are available for NM_015450.3:c.1884A>C. PS2 requires confirmation of de novo occurrence with both maternity and paternity confirmed.
PS3	Not met	No variant-specific functional studies have been performed for NM_015450.3:c.1884A>C. The ClinVar-cited publications (PMID:25741868, PMID:26467025) are methodology papers that do not contain any experimental data for this variant.
PS4	Not met	No case-control or prevalence data demonstrate a statistically significant enrichment of NM_015450.3:c.1884A>C in affected individuals compared to controls. The variant is common in the general population, which is inconsistent with a pathogenic role.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar classifies NM_015450.3:c.1884A>C as Benign (7 clinical laboratories). No reputable source has reported this variant as pathogenic.	clinvar
PM1	Not met	NM_015450.3:c.1884A>C is not located in a statistically significant mutational hotspot or a critical functional domain where benign variation is absent.
PM2	Not met	NM_015450.3:c.1884A>C is common in population databases. In gnomAD v2.1, total allele frequency is 1.07% (2980/279114 alleles) with 157 homozygotes, exceeding the PM2 threshold of <0.1%. In gnomAD v4.1, AF is 0.59% (9370/1588362 alleles) with 477 homozygotes. Highest subpopulation frequency is 11.1% in African/African American (v2.1). This variant is far too common to apply PM2.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a known pathogenic missense variant at the same amino acid residue. NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=) with no amino acid change, so there is no residue context for a missense comparator. pm5_candidates confirms not_applicable.	pm5_candidates
PM6	Not met	No de novo observation data are available for NM_015450.3:c.1884A>C. PM6 requires confirmation of de novo occurrence with maternity and paternity confirmed.
PP1	Not met	No co-segregation data are available for NM_015450.3:c.1884A>C. PP1 requires evidence of co-segregation with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=), not a missense variant.
PP3	Not met	In silico tools do not predict a damaging effect for NM_015450.3:c.1884A>C. REVEL score is 0.039 (low, predicted benign). SpliceAI max delta is 0.00 (no predicted splicing impact). Multiple lines of computational evidence suggest no functional consequence.	revel spliceai
PP4	Not met	No patient phenotype or clinical syndrome specificity data are available for NM_015450.3:c.1884A>C. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease.
PP5	Not met	ClinVar classifies NM_015450.3:c.1884A>C as Benign, not Pathogenic. No reputable source has reported this variant as pathogenic. PP5 requires a reputable source to report the variant as pathogenic with evidence unavailable for independent evaluation.	clinvar
BA1	Met	NM_015450.3:c.1884A>C is present at an allele frequency exceeding 1% in gnomAD. In gnomAD v2.1, the total AF is 1.07% (2980/279114 alleles) with 157 homozygotes observed. The grpmax filtering AF is 10.72% in the African/African American population. In gnomAD v4.1, the total AF is 0.59% with 477 homozygotes, and the grpmax FAF is 11.04%. The total AF in v2.1 exceeds the 1% BA1 threshold and is far above the ACMG/AMP 2015 threshold of 5% in the highest subpopulation. This frequency is incompatible with a rare Mendelian disease-causing variant.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not assessed	BS1 is superseded by BA1, which provides a stronger level of evidence (stand-alone benign vs. strong benign). The allele frequency already meets BA1 criteria; applying BS1 in addition would double-count the same population frequency evidence.
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. POT1 tumor predisposition syndrome (POT1-TPDS) is an adult-onset cancer predisposition syndrome with incomplete penetrance and variable expressivity. The presence of 157-477 homozygotes in gnomAD does not satisfy BS2 because the disorder does not have full penetrance at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	No variant-specific functional studies have been performed for NM_015450.3:c.1884A>C demonstrating no damaging effect on protein function or splicing. The ClinVar-cited publications (PMID:25741868, PMID:26467025) are methodology papers that contain no experimental data for this variant.
BS4	Not met	No data on lack of segregation are available for NM_015450.3:c.1884A>C. BS4 requires observation of the variant in a family member without the disease phenotype.
BP1	N/A	BP1 applies to missense variants in genes where the primary disease mechanism is through truncating variants. NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=), not a missense variant.
BP2	Not met	No data are available regarding co-occurrence of NM_015450.3:c.1884A>C in trans with a pathogenic POT1 variant (for a dominant disorder) or in cis with a pathogenic variant.
BP4	Not assessed	BP4 is not applied because BP7 is the more specific criterion for synonymous variants. BP4 and BP7 should not both be used for the same variant per ACMG/AMP 2015 guidelines, as they both rely on computational evidence. BP7 is applied instead.
BP5	Not met	No evidence is available that NM_015450.3:c.1884A>C is found in a case with an alternate molecular basis for disease. BP5 requires observation in a patient with an established alternative genetic cause.
BP6	Met	NM_015450.3:c.1884A>C is classified as Benign in ClinVar by 7 clinical laboratories (6 reporting 'Benign', 1 reporting 'benign'). Although individual submissions have review status 'criteria provided, single submitter', the concordance across multiple independent clinical laboratories provides supporting evidence for a benign classification.	clinvar
BP7	Met	NM_015450.3:c.1884A>C is a synonymous variant (p.Thr628=). SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is not highly conserved, as evidenced by the high population frequency (>10% in the African/African American population). BP7 criteria are satisfied: synonymous variant with no predicted splice impact at a non-conserved nucleotide.	spliceai gnomad_v2 gnomad_v4

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