Is MSH6 p.Ser2Ter (c.5C>A) pathogenic?

MSH6 p.Ser2Ter (c.5C>A) is classified Likely pathogenic in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Ser2Ter (c.5C>A)?

MSH6 p.Ser2Ter (c.5C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Ser2Ter (c.5C>A) in the general population?

MSH6 p.Ser2Ter (c.5C>A) is absent from gnomAD v4.1 (gnomAD).

MSH6 p.Ser2Ter

c.5C>A · VCV3913780

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 10
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 5.5	GERP 2, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH6
Protein: p.Ser2Ter
Coding: c.5C>A
MANE Select: NM_000179
Type: single nucleotide variant
Location: chr2:47783238 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 2: the 'disordered' region

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

Similar variants

MSH6 p.Ser2= Benign/Likely benign ★★ same residue
MSH6 p.Ser2Leu 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-ser2ter (accessed [today's date]).

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