Is PMS2 p.Ser517= (c.1551C>T) pathogenic?

PMS2 p.Ser517= (c.1551C>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-31). Very rare (popmax 0.00446%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ser517= (c.1551C>T) in the general population?

PMS2 p.Ser517= (c.1551C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

PMS2 p.Ser517=

Q: What condition is associated with PMS2 p.Ser517= (c.1551C>T)?

PMS2 p.Ser517= (c.1551C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.1551C>T · rs587782479 · VCV490093

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.74	donor gain · deltas
Pangolin	Δ0.82	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -1.3
Overall
CADD	16.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,614,026 alleles · very rare exomes 6/1,461,822 · genomes 0/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,437
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,012

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PMS2
Protein: p.Ser517=
Coding: c.1551C>T
MANE Select: NM_000535
dbSNP: rs587782479
Type: single nucleotide variant
Location: chr7:5987214 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 517: the 'disordered' region

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Ser517Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser517Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser517Ile Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser517Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pms2-p-ser517 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown