Is PMS2 p.Phe686= (c.2058T>C) pathogenic?

PMS2 p.Phe686= (c.2058T>C) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-03). Very rare (popmax 8.59e-05%, nfe); Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Phe686= (c.2058T>C)?

PMS2 p.Phe686= (c.2058T>C) is associated with Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Phe686= (c.2058T>C) in the general population?

PMS2 p.Phe686= (c.2058T>C) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PMS2 p.Phe686=

c.2058T>C · rs2128704052 · VCV1674222

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Conditions

Lynch syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	phastCons 0.81
Overall
CADD	6.657	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.59e-05% European (non-Finnish) · 1/1,164,008 alleles

Overall 6.96e-05% 1/1,437,472 alleles · very rare

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.Phe686=
Coding: c.2058T>C
MANE Select: NM_000535
dbSNP: rs2128704052
Type: single nucleotide variant
Location: chr7:5982940 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

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

Disease context

Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Phe686Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe686Tyr Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe686Cys Uncertain significance ★ ⚠ same residue
PMS2 p.Phe686Leu Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.705+1G>T 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-phe686 (accessed [today's date]).

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