NM_002439.5:c.2436-13G>T

MSH3 · NP_002430.3:p.? · NM_002439.5

GRCh37: chr5:80083371 G>T · GRCh38: chr5:80787552 G>T

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

BP4 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH3 c.2436-13G>T (p.?) variant has been reported in ClinVar as Likely benign.

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.

In silico splicing prediction does not support a damaging splice effect, with SpliceAI showing a maximum delta score of 0.02.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. The generic PVS1 assessment did not place this variant in a default null-variant category, so PVS1 is not applied.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid substitution. This variant is intronic and has no defined protein substitution, so PS1 is not applicable.
PS2	Not assessed	No de novo occurrence with confirmed maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional or RNA study showing a damaging effect of this specific variant was identified.
PS4	Not assessed	No case-control enrichment or affected-proband series establishing increased prevalence of this variant in affected individuals was identified. The variant is also present in population databases at measurable frequency, which does not support case enrichment from the available evidence.	gnomad_v2 gnomad_v4
PM1	N/A	PM1 is typically used for variants in a critical functional domain or mutational hotspot. This variant is intronic and no critical noncoding hotspot evidence was identified.
PM2	Not met	Population frequency does not support rarity for PM2. In gnomAD v4.1, the highest observed population frequency is 0.17028% in European non-Finnish individuals, which is above the default PM2 rarity threshold of 0.1%; gnomAD v2.1 also shows a highest population frequency of 0.14797%, also above 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual.
PM4	N/A	PM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants. This variant is intronic, so PM4 is not applicable.
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This variant is intronic and has no defined amino acid substitution, so PM5 is not applicable.
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified showing that this variant tracks with disease in affected family members.
PP2	N/A	PP2 is a missense-gene mechanism criterion and is not applicable to this intronic variant.
PP3	Not met	Available computational evidence does not support a deleterious splicing effect. SpliceAI shows a maximum delta score of 0.02, which is below commonly used thresholds for predicted splice disruption, and no REVEL or BayesDel score was available for this intronic variant.	spliceai
PP4	Not assessed	No phenotype information was provided that is sufficiently specific to MSH3-related disease to apply PP4.
PP5	Not assessed	A ClinVar classification is available, but no independently reviewable primary evidence was identified to support use of a source-only pathogenic criterion.	clinvar
BA1	Not met	The observed population frequency does not reach a stand-alone benign threshold. In gnomAD v4.1, the highest observed population frequency is 0.17028%, which is below the default BA1 threshold of 1.0%; gnomAD v2.1 shows 0.14797%, also below 1.0%.	gnomad_v2 gnomad_v4
BS1	Not met	The observed population frequency does not exceed the default strong benign threshold. In gnomAD v4.1, the highest observed population frequency is 0.17028%, which is below the default BS1 threshold of 0.3%; gnomAD v2.1 shows 0.14797%, also below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional or RNA study showing no damaging effect of this specific variant was identified.
BS4	Not assessed	No non-segregation data were identified showing that this variant fails to track with disease in informative families.
BP1	N/A	BP1 is a missense-specific criterion and is not applicable to this intronic variant.
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is intronic, so BP3 is not applicable.
BP4	Met	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
BP5	Not assessed	No alternate molecular explanation was identified that would establish this variant as occurring in a case with an independent cause of disease.
BP6	Not assessed	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.	clinvar
BP7	N/A	BP7 is not applied because this variant is intronic rather than synonymous, and no separate conservation-based noncoding rule was provided here.	spliceai

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