Is MSH6 p.Asp358= (c.1074C>T) pathogenic?

MSH6 p.Asp358= (c.1074C>T) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-23). Very rare (popmax 0.00223%, eas); Associated with Lynch syndrome 5.

What condition is associated with MSH6 p.Asp358= (c.1074C>T)?

MSH6 p.Asp358= (c.1074C>T) is associated with Lynch syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Asp358= (c.1074C>T) in the general population?

MSH6 p.Asp358= (c.1074C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Lynch syndrome inherited?

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

MSH6 p.Asp358=

c.1074C>T · rs760311819 · VCV385616

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Lynch syndrome 5

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 -2.6	GERP -3.8
Overall
CADD	2.988	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Overall 0.000137% 2/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	8.47e-05%	1,180,025

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: MSH6
Protein: p.Asp358=
Coding: c.1074C>T
MANE Select: NM_000179
dbSNP: rs760311819
Type: single nucleotide variant
Location: chr2:47799057 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 358: the 'disordered' region

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH6 p.Asp358Asn Uncertain significance ★★ ⚠ same residue
MSH6 p.Asp358His Uncertain significance ★★ ⚠ same residue
MSH6 p.Asp358Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Asp358Tyr Uncertain significance ★ ⚠ same residue
MSH6 p.Asp358fs Pathogenic ★ same residue
MSH6 p.Asp358Gly Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+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/msh6-p-asp358 (accessed [today's date]).

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