Starting

Initialising…

MSH6

Final classification

Uncertain Significance - Conflicting Evidence

MSH6 c.4T>A · p.Ser2Thr

MSH6

The MSH6 c.4T>A (p.Ser2Thr) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

Gene

MSH6

Transcript

NM_000179.3

HGVS · transcript:coding

NM_000179.3:c.4T>A

Consequence

N/A

GRCh38

chr2:47783237 T>A

GRCh37

chr2:48010376 T>A

Basis ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence. ▾

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.

Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

MSH6 c.4T>A

The MSH6 c.4T>A (p.Ser2Thr) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v4.1 and gnomAD v2.1, which meets the MSH6 VCEP PM2 threshold for supporting evidence because the observed allele frequency is below 0.00002.² For this MSH6 missense variant, the HCI prior probability is 0.0038, below the BP4 threshold of 0.11 and consistent with benign computational evidence; REVEL is 0.405 and BayesDel is -0.114406.³

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 hci_priorrevelbayesdelcspec ↗

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

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 v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.405. BayesDel score = -0.114406. HCI prior probability for pathogenicity = 0.0038. MAPP score = 3.15. Custom PP2 score = 0.243.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots