Is MLH1 p.Ser87= (c.261C>T) pathogenic?

MLH1 p.Ser87= (c.261C>T) is classified Benign/Likely benign in MLH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-05-19). Very rare (popmax 0.000339%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MLH1 p.Ser87= (c.261C>T)?

MLH1 p.Ser87= (c.261C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is MLH1 p.Ser87= (c.261C>T) in the general population?

MLH1 p.Ser87= (c.261C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

MLH1 p.Ser87=

c.261C>T · rs63750923 · VCV219994

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	phastCons 0.085
Overall
CADD	10.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,178,726 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,378 alleles · very rare exomes 3/1,460,412 · genomes 1/151,966 · 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: MLH1
Protein: p.Ser87=
Coding: c.261C>T
MANE Select: NM_000249
dbSNP: rs63750923
Type: single nucleotide variant
Location: chr3:37001008 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB

Full MLH1 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 2 hereditary neoplastic syndrome

Similar variants

MLH1 p.Ser87Cys Uncertain significance ★★ ⚠ same residue
MLH1 p.Ser87Phe Uncertain significance ★ ⚠ same residue
MLH1 p.Ser87Pro Uncertain significance ★ ⚠ same residue
MLH1 p.Ser87Ala Uncertain significance ★ ⚠ same residue
MLH1 c.1038+1G>C Likely pathogenic ★★★ same condition
MLH1 c.1039-1G>A Pathogenic ★★★ same condition
MLH1 c.1039-2A>G Likely pathogenic ★★★ same condition
MLH1 c.1039-2A>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/mlh1-p-ser87 (accessed [today's date]).

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