Is MSH6 p.Ser541= (c.1623C>T) pathogenic?

MSH6 p.Ser541= (c.1623C>T) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-17). Very rare (popmax 0.005%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Ser541= (c.1623C>T)?

MSH6 p.Ser541= (c.1623C>T) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Ser541= (c.1623C>T) in the general population?

MSH6 p.Ser541= (c.1623C>T) is very rare (popmax 0.005%, amr) (gnomAD).

MSH6 p.Ser541=

c.1623C>T · rs777678406 · VCV416138

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 0.4	GERP -1.6, phastCons 0.96
Overall
CADD	7.934	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,614,082 alleles · very rare exomes 6/1,461,884 · genomes 0/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,002
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,002

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.Ser541=
Coding: c.1623C>T
MANE Select: NM_000179
dbSNP: rs777678406
Type: single nucleotide variant
Location: chr2:47799606 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 541: a β-strand

Full MSH6 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 5

Similar variants

MSH6 p.Ser541Arg Likely pathogenic ★★★ same residue
MSH6 p.Ser541Gly Conflicting classifications of pathogenicity ★ ⚠ 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-ser541 (accessed [today's date]).

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