Is PMS2 p.Ser7Leu (c.20C>T) pathogenic?

PMS2 p.Ser7Leu (c.20C>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1054); Very rare (popmax 6.2e-05%); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ser7Leu (c.20C>T) in the general population?

PMS2 p.Ser7Leu (c.20C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about PMS2 p.Ser7Leu (c.20C>T)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

PMS2 p.Ser7Leu

Q: What condition is associated with PMS2 p.Ser7Leu (c.20C>T)?

PMS2 p.Ser7Leu (c.20C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, breast cancer, Lynch syndrome 4 (ClinVar).

c.20C>T · rs587780048 · VCV127772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	10.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,612,632 alleles · very rare exomes 1/1,460,306 · genomes 0/152,326 · joint denominator

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.Ser7Leu
Coding: c.20C>T
MANE Select: NM_000535
dbSNP: rs587780048
Type: single nucleotide variant
Location: chr7:6009000 (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

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

Also linked: breast cancer Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Ser7Ter Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Ser7Trp Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser7= Benign/Likely benign ★★ same residue
PMS2 p.Ser7Pro 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-ser7leu (accessed [today's date]).

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