Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

MSH6 c.4002-17T>C

The MSH6 c.4002-17T>C (NP_000170.1:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada, supporting rarity below the MSH6 PM2 threshold of less than 0.00002.² SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, which is below the MSH6 BP4 threshold of less than or equal to 0.1 and below the PP3 threshold of greater than or equal to 0.2 for non-canonical splice variants.³

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗cspec ↗

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

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada. Its observed population frequency is therefore below the MSH6 PM2 threshold of less than 0.00002 (fewer than 1 in 50,000 alleles), supporting rarity.

gnomAD v4.1: absentgnomAD v2.1: absentgnomAD-Canada v1.0: absent

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

✓

BP4 supporting Benign

SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04. This is below the MSH6 BP4 threshold of less than or equal to 0.1 and supports no predicted splicing effect.

SpliceAI max delta score: 0.04MSH6 BP4 threshold for intronic/synonymous variants: <=0.1

spliceai ↗cspec ↗

Assessed · not applied

Pathogenic

PVS1 Although loss of function is an established disease mechanism for MSH6, this variant is a non-canonical intronic change at c.4002-17 and does not fall within the default PVS1 null-variant categories.

PS1 No pathogenic or likely pathogenic comparator affecting the same non-canonical splice nucleotide was identified in the available evidence, so PS1 could not be applied.

PS2 No de novo data were identified for this variant, so PS2 could not be assessed.

PS3 No calibrated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 could not be assessed.

PM3 No data were identified showing this variant in trans with another pathogenic MSH6 variant in a constitutional mismatch repair deficiency setting, so PM3 could not be assessed.

PP1 No segregation data were identified for this variant, so PP1 could not be assessed.

PP3 SpliceAI does not support a predicted splice defect for this non-canonical intronic variant.

PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry data were identified, so PP4 could not be assessed.

Benign

BA1 This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BA1 threshold of filtering allele frequency greater than or equal to 0.0022 (0.22%).

BS1 This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BS1 frequency range of 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 older individual without features of constitutional mismatch repair deficiency were identified, so BS2 could not be assessed.

BS3 No variant-specific RNA or functional assay data showing normal splicing or retained function were identified, so BS3 could not be assessed.

BS4 No non-segregation data were identified for this variant, so BS4 could not be assessed.

BP5 No tumor data showing microsatellite-stable disease, retained mismatch repair protein expression, or gene-inconsistent loss of mismatch repair proteins were identified, so BP5 could not be assessed.

BP7 This is an intronic variant at c.4002-17, which is 17 nucleotides from the exon boundary and does not meet the MSH6 BP7 distance requirement for variants at or beyond -21 or +7.

N/A · 11 PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Re-run this variant?