Is MSH2 p.Phe539= (c.1617T>C) pathogenic?

MSH2 p.Phe539= (c.1617T>C) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-01). Very rare (popmax 0.00102%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Phe539= (c.1617T>C)?

MSH2 p.Phe539= (c.1617T>C) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Phe539= (c.1617T>C) in the general population?

MSH2 p.Phe539= (c.1617T>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

MSH2 p.Phe539=

c.1617T>C · rs730881759 · VCV379028

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

hereditary neoplastic syndrome

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 -1.4	GERP -4.1
Overall
CADD	5.223	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,896 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,830 alleles · very rare exomes 10/1,461,624 · genomes 2/152,206 · 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: MSH2
Protein: p.Phe539=
Coding: c.1617T>C
MANE Select: NM_000251
dbSNP: rs730881759
Type: single nucleotide variant
Location: chr2:47466764 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Lynch syndrome Lynch syndrome 1 Muir-Torre syndrome mismatch repair cancer syndrome 2

Similar variants

MSH2 p.Phe539Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Phe539Cys Uncertain significance ★ ⚠ same residue
MSH2 p.Phe539Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Phe539Val Uncertain significance ★ ⚠ same residue
MSH2 p.Phe539Tyr Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C 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/msh2-p-phe539 (accessed [today's date]).

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