Is MSH2 p.Ser515= (c.1545C>T) pathogenic?

MSH2 p.Ser515= (c.1545C>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-05-21). Very rare (popmax 0.000254%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser515= (c.1545C>T)?

MSH2 p.Ser515= (c.1545C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser515= (c.1545C>T) in the general population?

MSH2 p.Ser515= (c.1545C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

MSH2 p.Ser515=

c.1545C>T · rs1553366537 · VCV455506

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 0.33	GERP 0.23, phastCons 0.99
Overall
CADD	9.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,954 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,964 alleles · very rare exomes 3/1,461,770 · genomes 0/152,194 · 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.Ser515=
Coding: c.1545C>T
MANE Select: NM_000251
dbSNP: rs1553366537
Type: single nucleotide variant
Location: chr2:47466692 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 515: a β-strand

Full MSH2 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 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser515Cys Uncertain significance ★ ⚠ same residue
MSH2 p.Ser515Tyr Uncertain significance ★ ⚠ same residue
MSH2 p.Ser515fs Pathogenic ★ 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
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C 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-ser515 (accessed [today's date]).

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