Starting

Initialising…

MSH6

Final classification

VUS

MSH6 c.3556+1G>C · p.?

MSH6

The MSH6 NM_000179.3:c.3556+1G>C (NP_000170.1:p.?) variant has been reported in ClinVar as Pathogenic by a single clinical laboratory.

Gene

MSH6

Transcript

NM_000179.3

HGVS · transcript:coding

NM_000179.3:c.3556+1G>C

Consequence

N/A

GRCh38

chr2:47805028 G>C

GRCh37

chr2:48032167 G>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 was evaluated deterministically with applied criteria: PM2 supporting, PVS1 very strong; no rule matched the adjudicated criteria. ▾

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 was evaluated deterministically with applied criteria: PM2 supporting, PVS1 very strong; no rule matched the adjudicated criteria.

Classification rationale

PM2PVS1 VUS

MSH6 c.3556+1G>C

The MSH6 NM_000179.3:c.3556+1G>C (NP_000170.1:p.?) variant has been reported in ClinVar as Pathogenic by a single clinical laboratory.¹ This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002.² This canonical +1 splice-donor variant is predicted to disrupt splicing, with SpliceAI showing a maximum delta score of 1.00, and the MSH6 VCEP PVS1 framework supports very strong pathogenic evidence for canonical splice variants expected to cause a frameshifting transcript subject to nonsense-mediated decay.³

PM2 + PVS1 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗pvs1_gene_contextpvs1_variant_assessment

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

This variant is present in gnomAD v4.1 (AF= 1.24445e-06; MAF= 0.00012%, 2/1607140 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60653e-05; MAF= 0.00161%, 1/62246 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,607,140
0 hom

Remaining individuals 1 / 62,246	0.0016%
European (non-Finnish) 1 / 1,173,668	8.5e-05%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 Pathogenic (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.325996.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC