MSH6

Final classification

Unclassified

MSH6 c.1796G>A · p.Gly599Glu

MSH6

The variant NM_000179.2:c.1796G>A (p.Gly599Glu) in MSH6 is a missense substitution absent from all gnomAD population databases (PM2_Supporting).

Gene

MSH6

Transcript

NM_000179.2

HGVS · transcript:coding

NM_000179.2:c.1796G>A

Consequence

N/A

exon NC_000002.11

GRCh38

chr2:47799779 G>A

GRCh37

chr2:48026918 G>A

Classification rationale

PM2PP3 Unclassified

MSH6 c.1796G>A · exon NC_000002.11

The variant NM_000179.2:c.1796G>A (p.Gly599Glu) in MSH6 is a missense substitution absent from all gnomAD population databases (PM2_Supporting).¹ In silico prediction supports a deleterious effect: HCI prior probability for pathogenicity is 0.9346, meeting the MSH6 VCEP threshold for PP3_Moderate (>0.81). REVEL score is 0.807, also consistent with a damaging prediction.² No functional assay data, segregation data, or tumor phenotype data are available for this variant. The variant has not been reported in ClinVar with expert panel review (currently Uncertain significance, 1-star).³ Multiple VCEP criteria are marked Not Applicable (PP5, BP6, PM1, PP2, PS4, PM6, BP1, BP2) as per the InSiGHT MSH6 VCEP v2.0 framework.⁴

PM2 + PP3 → Unclassified

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 hci_priorcspec ↗

3 clinvar ↗

4 cspec ↗

Gene diagram · NM_000179.2 · variants mapped to exon structure

MSH6 NM_000179.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the InSiGHT MSH6 VCEP threshold for PM2_Supporting (allele frequency < 0.00002, i.e., <1 in 50,000 alleles).

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

✓

PP3 moderate Pathogenic

The HCI prior probability for pathogenicity is 0.9346, which exceeds the InSiGHT MSH6 VCEP threshold of >0.81 for PP3_Moderate in missense variants.

HCI prior probability = 0.9346 (>0.81 threshold for PP3_Moderate).REVEL score = 0.807 (supportive).SpliceAI max delta = 0.00 (no predicted splice impact).

cspec ↗

Assessed · not applied

Pathogenic

PS1 No different nucleotide change encoding the same amino acid substitution (Gly599Glu) has been previously classified as Pathogenic or Likely Pathogenic by this VCEP.

PS2 No de novo occurrence data are available for this variant.

PS3 No variant-specific functional assay data or calibrated functional odds for pathogenicity are available for c.1796G>A (p.Gly599Glu).

PM5 No different missense change at amino acid residue Gly599 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MSH6 VCEP.

PP1 No co-segregation data with Bayes likelihood ratios are available for this variant.

PP4 No MSI-H tumor data or MMR protein immunohistochemistry results are available for this variant.

Benign

BA1 The variant is absent from all gnomAD population databases.

BS1 The variant is absent from all gnomAD population databases.

BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD.

BS3 No calibrated functional assay data with functional odds for pathogenicity ≤ 0.05 (BS3_Strong) or ≤ 0.48 (BS3_Supporting) are available for this variant.

BS4 No co-segregation data are available to evaluate lack of co-segregation with disease.

BP4 The HCI prior probability for pathogenicity is 0.9346, which substantially exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of < 0.11.

BP5 No tumor data (MSS status, MMR IHC, BRAF V600E mutation, MLH1 methylation) are available for this variant to support a benign interpretation.

N/A · 11 PVS1 · PS4 · PM1 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

In progress — evidence not uploaded yet.

ClinVar ↗

In silico

In progress — evidence not uploaded yet.

SpliceAI ↗

Functional Unknown Oncogenic Effect

In progress — evidence not uploaded yet.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

In progress — evidence not uploaded yet.

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR