Starting

Initialising…

MSH6

Final classification

Likely Benign

MSH6 c.2091T>C · p.Asp697=

MSH6

The MSH6 c.2091T>C (p.Asp697=) variant has not been observed in somatic cancers in COSMIC.

Gene

MSH6

Transcript

NM_000179.3

HGVS · transcript:coding

NM_000179.3:c.2091T>C

Consequence

N/A

GRCh38

chr2:47800074 T>C

GRCh37

chr2:48027213 T>C

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 Rule19 (Benign.Supporting >=2) with applied criteria: BP7 supporting, PM2 supporting, BP4 supporting; maps to Likely Benign. ▾

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 Rule19 (Benign.Supporting >=2) with applied criteria: BP7 supporting, PM2 supporting, BP4 supporting; maps to Likely Benign.

Classification rationale

PM2 BP7BP4 Likely Benign

MSH6 c.2091T>C

The MSH6 c.2091T>C (p.Asp697=) variant has not been observed in somatic cancers in COSMIC. This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its gnomAD v4.1 frequency is therefore below the MSH6 PM2_Supporting threshold of less than 0.00002.¹ This synonymous exon 4 variant is far from the splice junction boundaries used for MSH6 BP7, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.02, supporting BP7 and BP4 while arguing against PP3 or PVS1 based on the currently available evidence.²

PM2 + BP7 + BP4 → Likely Benign

1 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

2 spliceai ↗cspec ↗pvs1_variant_assessment

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · supports benign

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 has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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