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

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 · 3 applied · 15 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 · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1, which is below the MSH6 PM2_Supporting threshold of less than 0.00002 (less than 1 in 50,000 alleles).

gnomAD v4.1: absent

gnomad_v4 ↗cspec ↗

BP4 supporting Benign

For this synonymous variant, SpliceAI predicts no meaningful splicing impact with a maximum delta score of 0.02, which is below the MSH6 BP4 threshold of 0.1 or less. This supports BP4.

SpliceAI max delta score 0.02

spliceai ↗cspec ↗

BP7 supporting Benign

This is a synonymous variant, NM_000179.3:p.(Asp697=), located in exon 4 at c.2091, which is far beyond the MSH6 BP7 boundary requirement of -21/+7 from the splice junctions. This supports BP7.

Synonymous change p.(Asp697=)c.2091 lies within exon 4 (c.628-c.3172)

cspec ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PVS1 This variant is a synonymous substitution, p.(Asp697=), and does not fall into the MSH6 PVS1 categories for nonsense, frameshift, canonical +/-1 or 2 splice, initiation codon, or proven loss-of-function splicing variants.

PS1 No evidence was identified that this variant affects the same non-canonical splice nucleotide as a previously established pathogenic or likely pathogenic splice variant with similar or worse predicted splicing impact, so PS1 was not assessed.

PS2 No confirmed or assumed de novo data were identified, so PS2 cannot be assessed.

PS3 No calibrated damaging functional assay and no variant-specific RNA evidence demonstrating an abnormal splicing effect were identified, so PS3 cannot be applied.

PM3 No evidence was identified for co-occurrence with another pathogenic or likely pathogenic MSH6 variant in a context meeting the CMMRD-based PM3 scoring framework.

PM5 This is not a missense change, and no qualifying pathogenic or likely pathogenic missense comparator at the same residue was identified for PM5 assessment.

PP1 No segregation data were identified, so PP1 cannot be applied.

PP3 This variant is not a missense substitution, so the MSH6 HCI-prior missense thresholds do not apply.

PP4 No tumor microsatellite instability results, mismatch repair immunohistochemistry results, or phenotype data meeting the MSH6 PP4 thresholds were identified.

Benign

BA1 This variant is absent from gnomAD v4.1, so it does not meet the MSH6 BA1 threshold of group maximum filtering allele frequency greater than or equal to 0.22%.

BS1 This variant is absent from gnomAD v4.1, so it does not meet the MSH6 BS1 threshold of group maximum filtering allele frequency greater than or equal to 0.00022 and less than 0.0022.

BS2 No co-occurrence data in trans with a known pathogenic MSH6 variant in an individual lacking clinical features of CMMRD were identified, so BS2 cannot be assessed from the available evidence.

BS3 No variant-specific RNA study with nonsense-mediated decay inhibition and no calibrated functional assay demonstrating no damaging effect were identified, so BS3 cannot be applied.

BS4 No family data showing lack of segregation with disease were identified, so BS4 cannot be assessed.

BP5 No tumor evidence showing a pattern inconsistent with MSH6-related mismatch repair deficiency and no alternate molecular explanation meeting the MSH6 BP5 thresholds were identified.

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

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

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