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

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 · 2 applied · 13 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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

This variant affects the canonical +1 splice donor position of MSH6. The MSH6 VCEP PVS1 rule allows very strong evidence for IVS±1/2 variants when the predicted splice outcome disrupts the reading frame and is expected to undergo nonsense-mediated decay, and the affected donor corresponds to exon 6, whose skipping would be out of frame. SpliceAI also predicts a strong splice effect with a max delta score of 1.00, supporting disruption of normal splicing.

Canonical splice donor variant c.3556+1G>CMSH6 loss of function established in the VCEP frameworkGeneric PVS1 scaffold marks a canonical splice variant and advises not to stack PP3

cspec ↗spliceai ↗

PM2 supporting review Pathogenic

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 (<1 in 50,000 alleles), supporting PM2 at supporting strength.

gnomAD v2.1 absentgnomAD v4.1 total AF 1.24445e-06 (2/1607

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS2 No de novo data were identified for this variant, so PS2 cannot be applied.

PS3 No validated RNA study or calibrated functional assay was identified for this exact variant showing an abnormal MSH6 effect, so PS3 cannot be applied at this time.

PM3 No data were identified showing this variant in trans with another MSH6 pathogenic or likely pathogenic variant in a proband meeting the VCEP PM3 framework, so PM3 was not applied.

PP1 No segregation data were identified, so there is no Bayes likelihood ratio available to support PP1.

PP4 No microsatellite instability or mismatch repair immunohistochemistry data were identified for this variant, so the tumor phenotype-specific PP4 rule cannot be applied.

Benign

BA1 The gnomAD v4.1 total allele frequency is 1.24445e-06 (0.00012%), which is below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%), so this frequency does not support a benign stand-alone classification.

BS1 The highest observed gnomAD v4.1 population allele frequency is 1.60653e-05 (0.00161%) in Remaining individuals, which is below the BS1 range of 0.00022 to <0.0022, so the population data do not support BS1.

BS2 No evidence was identified showing this variant in trans with a known pathogenic MSH6 variant in an individual meeting the VCEP BS2 conditions and lacking evidence of CMMRD.

BS3 No RNA or functional assay evidence was identified showing normal splicing or preserved MSH6 function for this variant, so BS3 cannot be applied.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied.

BP4 SpliceAI predicts a strong splice effect with a max delta score of 1.00, which is above the MSH6 VCEP BP4 no-impact threshold of 0.1 for intronic variants.

BP5 No tumor findings inconsistent with MSH6-related disease were identified, so BP5 was not applied.

BP7 This intronic variant is at the +1 canonical splice donor position, not at or beyond the BP7 boundary of +7, so it does not meet the MSH6 VCEP BP7 rule.

N/A · 13 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · 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= 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

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