Is MSH2 p.Asp654= (c.1962C>T) pathogenic?

MSH2 p.Asp654= (c.1962C>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-17). Very rare (popmax 0.00501%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Asp654= (c.1962C>T)?

MSH2 p.Asp654= (c.1962C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Asp654= (c.1962C>T) in the general population?

MSH2 p.Asp654= (c.1962C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

MSH2 p.Asp654=

c.1962C>T · rs751939698 · VCV379029

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.18	GERP -4.1, phastCons 0.66
Overall
CADD	8.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,860 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.00105% 17/1,612,452 alleles · very rare exomes 14/1,461,664 · genomes 3/150,788 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,953
Remaining individualsnot grpmax-eligible	0.0016%	62,442
South Asian	0.0011%	91,048
European (non-Finnish)	0.00102%	98,318

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.Asp654=
Coding: c.1962C>T
MANE Select: NM_000251
dbSNP: rs751939698
Type: single nucleotide variant
Location: chr2:47475227 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 654: the 'interaction with exo1' region; 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.Asp654Glu Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp654Val Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp654Gly Uncertain significance ★ ⚠ same residue
MSH2 p.Asp654Asn Likely benign ★ ⚠ same residue
MSH2 p.Asp654fs 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

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-asp654 (accessed [today's date]).

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