Is MSH6 p.Phe340Ser (c.1019T>C) pathogenic?

MSH6 p.Phe340Ser (c.1019T>C) is classified Likely benign in MSH6 (ClinVar, Expert panel, 14 submitters; last evaluated 2013-09-05). AlphaMissense: ambiguous (0.5329); Ultra-rare (popmax 0.0114%, nfe); Associated with Lynch syndrome.

What condition is associated with MSH6 p.Phe340Ser (c.1019T>C)?

MSH6 p.Phe340Ser (c.1019T>C) is associated with Lynch syndrome, endometrial carcinoma, Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Phe340Ser (c.1019T>C) in the general population?

MSH6 p.Phe340Ser (c.1019T>C) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about MSH6 p.Phe340Ser (c.1019T>C)?

AlphaMissense predicts ambiguous (score 0.5329) — an in-silico prediction, not a clinical call.

MSH6 p.Phe340Ser

c.1019T>C · rs61753793 · VCV89165

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

ambiguous

0.5329 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.5329	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -3.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.74, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0114% European (non-Finnish) · 135/1,180,046 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.00911% 147/1,614,104 alleles · ultra-rare exomes 138/1,461,880 · genomes 9/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.0114%	8,741
Admixed American	0.00333%	30,006
African / African-American	0.00133%	74,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe340Ser
Coding: c.1019T>C
MANE Select: NM_000179
dbSNP: rs61753793
Type: single nucleotide variant
Location: chr2:47799002 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 340: the 'disordered' region; a UniProt-annotated variant site (in)

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

Disease context

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

Also linked: endometrial carcinoma Lynch syndrome 5 hereditary neoplastic syndrome mismatch repair cancer syndrome 3

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH6 p.Phe340= Benign ★ same residue
MSH6 p.Phe340Leu Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>G Likely pathogenic ★★★ same condition
MSH6 c.3647-1G>A Pathogenic ★★★ same condition
MSH6 c.3647-2A>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/msh6-p-phe340ser (accessed [today's date]).

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