Is PMS2 p.Asp557= (c.1671T>C) pathogenic?

PMS2 p.Asp557= (c.1671T>C) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00267%, afr); Associated with mismatch repair cancer syndrome 4.

What condition is associated with PMS2 p.Asp557= (c.1671T>C)?

PMS2 p.Asp557= (c.1671T>C) is associated with mismatch repair cancer syndrome 4, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Asp557= (c.1671T>C) in the general population?

PMS2 p.Asp557= (c.1671T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

PMS2 p.Asp557=

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.1671T>C · rs1554297386 · VCV492267

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

mismatch repair cancer 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 -1.3
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,040 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000342% 5/1,461,852 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,520
South Asian	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Asp557=
Coding: c.1671T>C
MANE Select: NM_000535
dbSNP: rs1554297386
Type: single nucleotide variant
Location: chr7:5987094 (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

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

Also linked: Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PMS2 p.Asp557Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Asp557Glu Uncertain significance ★ ⚠ same residue
PMS2 p.Asp557Val Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Asp557Tyr Uncertain significance ★ ⚠ 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-asp557 (accessed [today's date]).

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