Classification rationale

BP4 VUS

MSH3 c.2436-13G>T

The MSH3 c.2436-13G>T (p.?) variant has been reported in ClinVar as Likely benign.¹ This variant is present in population databases, including gnomAD v2.1 at 0.07852% overall with a highest observed population frequency of 0.14797% and gnomAD v4.1 at 0.13248% overall with a highest observed population frequency of 0.17028%, which is above a default PM2 rarity threshold of 0.1% but below default BS1 and BA1 thresholds.² In silico splicing prediction does not support a damaging splice effect, with SpliceAI showing a maximum delta score of 0.02.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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_002439.5 · variants mapped to exon structure

MSH3 NM_002439.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 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

BP4 supporting review Benign

Computational evidence supports no meaningful impact on splicing. SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, which argues against a damaging splice alteration for this noncanonical intronic variant.

SpliceAI max delta score 0.02 with low individual donor and acceptor delta scores.

spliceai ↗

Assessed · not applied · 5 not met · 14 not assessed

Pathogenic

PVS1 Loss of function is considered a relevant disease mechanism for MSH3, but this intronic variant is at c.2436-13 and is outside the canonical +/-1,2 splice consensus positions.

PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant.

PS3 No well-established functional or RNA study showing a damaging effect of this specific variant was identified.

PS4 No case-control enrichment or affected-proband series establishing increased prevalence of this variant in affected individuals was identified.

PM2 Population frequency does not support rarity for PM2.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual.

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified showing that this variant tracks with disease in affected family members.

PP3 Available computational evidence does not support a deleterious splicing effect.

PP4 No phenotype information was provided that is sufficiently specific to MSH3-related disease to apply PP4.

PP5 A ClinVar classification is available, but no independently reviewable primary evidence was identified to support use of a source-only pathogenic criterion.

Benign

BA1 The observed population frequency does not reach a stand-alone benign threshold.

BS1 The observed population frequency does not exceed the default strong benign threshold.

BS2 Homozygotes are present in gnomAD, but the available evidence here does not establish whether unaffected homozygous occurrence is sufficiently informative for this gene-disease context to support BS2.

BS3 No well-established functional or RNA study showing no damaging effect of this specific variant was identified.

BS4 No non-segregation data were identified showing that this variant fails to track with disease in informative families.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant condition or in cis with a pathogenic variant in an informative setting.

BP5 No alternate molecular explanation was identified that would establish this variant as occurring in a case with an independent cause of disease.

BP6 This variant is reported in ClinVar as Likely benign, but no independently reviewable primary evidence was available here to support a source-only benign criterion.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00132477; MAF= 0.13248%, 2106/1589706 alleles, homozygotes = 5) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00170283; MAF= 0.17028%, 1972/1158070 alleles, homozygotes = 5); grpmax FAF= 0.00164017.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000785157; MAF= 0.07852%, 222/282746 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00147968; MAF= 0.14797%, 191/129082 alleles, homozygotes = 1); grpmax FAF= 0.00136914.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.13% · 2106 / 1,589,706
5 hom · FAF 0.16%

European (non-Finnish) 1972 / 1,158,070	0.17% 5 hom
Remaining individuals 64 / 61,670	0.1%
Admixed American 29 / 59,934	0.048%
Ashkenazi Jewish 14 / 29,444	0.048%
African/African American 17 / 74,390	0.023%
European (Finnish) 8 / 63,950	0.013%
South Asian 2 / 90,610	0.0022%

+ 3 not observed (Amish, East Asian, Middle Eastern)

gnomAD v2.1

0.079% · 222 / 282,746
1 hom · FAF 0.14%

European (non-Finnish) 191 / 129,082	0.15% 1 hom
Ashkenazi Jewish 6 / 10,368	0.058%
Remaining individuals 3 / 7,220	0.042%
Admixed American 13 / 35,420	0.037%
African/African American 6 / 24,966	0.024%
European (Finnish) 3 / 25,120	0.012%

+ 2 not observed (East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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