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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is extremely rare in population databases. In gnomAD v4.1, it is present in 1/1,501,316 alleles (AF 6.66082e-07), which is below the MSH6 PM2_Supporting threshold of 0.00002.

gnomAD v4.1 total AF 6.66082e-07MSH6 PM2 threshold is <0.00002

gnomad_v4 ↗cspec ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Pro67Thr), and does not create a premature termination codon or canonical splice-site change.

PS1 No evidence was identified that the same amino acid change, p.(Pro67Thr), has previously been established by this VCEP as pathogenic or likely pathogenic due to a different nucleotide change.

PS2 No de novo observation was identified for this variant.

PS3 No variant-specific functional study was identified showing mismatch repair deficiency or pathogenic functional odds that would satisfy the MSH6 VCEP PS3 rule.

PM3 No evidence was identified that this variant occurred with another pathogenic MSH6 variant in a configuration and clinical setting that would generate PM3 points.

PM5 No evidence was identified that a different missense change at codon 67 has been established by this VCEP as pathogenic or likely pathogenic on the protein level and independent of splicing.

PP1 No segregation data were identified for this variant.

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), REVEL is 0.161, and BayesDel is -0.32103, which do not support a damaging computational profile.

PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry data were identified for this variant.

Benign

BA1 Population frequency does not meet the MSH6 BA1 threshold.

BS1 Population frequency does not meet the MSH6 BS1 threshold.

BS2 No evidence was identified that this variant occurred in trans with a known pathogenic MSH6 variant in an individual meeting the VCEP clinical conditions for BS2.

BS3 No variant-specific functional study was identified showing retained mismatch repair function or a benign RNA result that would satisfy the MSH6 VCEP BS3 rule.

BS4 No non-segregation data were identified for this variant.

BP4 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).

BP5 No tumor findings were identified showing microsatellite stable disease, intact mismatch repair expression, or mismatch between tumor pattern and the gene involved.

BP7 This is a missense variant, p.(Pro67Thr), rather than a synonymous or qualifying intronic variant.

N/A · 10 PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

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

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