Classification rationale

PM2 VUS

MSH6 c.199C>A

The MSH6 c.199C>A (p.Pro67Thr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with mostly uncertain significance submissions and one benign submission.¹ This variant is extremely rare in gnomAD v4.1, where it is present in 1 of 1,501,316 alleles (AF 6.66082e-07) with a highest observed population frequency of 8.86721e-07 in non-Finnish Europeans, which is below the MSH6 PM2_Supporting threshold of 0.00002.² SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational scores are low or benign-leaning (REVEL 0.161; BayesDel -0.32103), although the MSH6 VCEP missense PP3/BP4 rule requires an HCI prior probability that was not available here.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

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= 6.66082e-07; MAF= 0.00007%, 1/1501316 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.86721e-07; MAF= 0.00009%, 1/1127750 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 9.50408e-06; MAF= 0.00095%, 1/105218 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.31267e-05; MAF= 0.00231%, 1/43240 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.7e-05% · 1 / 1,501,316
0 hom

European (non-Finnish)

1 / 1,127,750

8.9e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00095% · 1 / 105,218
0 hom

European (non-Finnish)

1 / 43,240

0.0023%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.161. BayesDel score = -0.32103.

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