About MSH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH3 c.2436-13G>T, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting; combination = 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2,106 / 1,589,706 alleles
gnomAD v4.1: 2,106 / 1,589,706 alleles. Recorded AF 0.00132477. Recorded homozygote count 5.
gnomAD 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.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 14 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 1
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
BP4 was applied as supporting benign computational evidence against splice disruption.
Evidence considered
- SpliceAI max delta score 0.02 with low individual donor and acceptor delta scores.
Still missing
- No additional splice-function assay was available.
Sources
Not met · 5 · evaluated, threshold not reached
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. The generic PVS1 assessment did not place this variant in a default null-variant category, so PVS1 is not applied. Details ▾Hide ▴
Rule
Generic PVS1 fallback may be considered only when loss of function is an established mechanism and the variant meets an eligible null-variant framework; that framework was not met here.
Evidence considered
- MSH3 was flagged as eligible for generic PVS1 consideration at the gene level.
- The variant-level PVS1 scaffold classified c.2436-13G>T as noncanonical intronic and outside the default generic PVS1 buckets.
Still missing
- Variant-specific RNA evidence would be needed to show a proven truncating or loss-of-function splicing effect despite the noncanonical intronic position.
Sources
PM2 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%. Details ▾Hide ▴
Rule
Default non-VCEP rarity threshold considered: PM2 if population frequency is below 0.1%.
Evidence considered
- gnomAD v2.1 best-subpopulation AF 0.00147968.
- gnomAD v4.1 best-subpopulation AF 0.00170283.
Sources
PP3 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. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect; that support was not present here.
Evidence considered
- SpliceAI DS_AG 0.01
- DS_AL 0.02
- DS_DG 0.00
- DS_DL 0.00
- max delta 0.02.
- REVEL not found.
- BayesDel not found.
Still missing
- Additional validated splice predictors or RNA data could further clarify the splicing effect.
Sources
BA1 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%. Details ▾Hide ▴
Rule
Default non-VCEP benign stand-alone threshold considered: BA1 if population frequency is above 1.0%.
Evidence considered
- gnomAD v2.1 best-subpopulation AF 0.00147968.
- gnomAD v4.1 best-subpopulation AF 0.00170283.
Sources
BS1 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%. Details ▾Hide ▴
Rule
Default non-VCEP benign strong threshold considered: BS1 if population frequency is above 0.3%.
Evidence considered
- gnomAD v2.1 best-subpopulation AF 0.00147968.
- gnomAD v4.1 best-subpopulation AF 0.00170283.
Sources
Not assessed · 14 · no assessment recorded
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
- Trio-based case data with confirmed parentage would be needed.
PS3 No well-established functional or RNA study showing a damaging effect of this specific variant was identified. Details ▾Hide ▴
Still missing
- Direct RNA or splicing assay data for c.2436-13G>T would be needed.
PS4 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. Details ▾Hide ▴
Evidence considered
- The variant is present in gnomAD v2.1 and v4.1.
Still missing
- Exact affected-proband counts and a formal comparison with ancestry-matched controls would be needed.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual. Details ▾Hide ▴
Still missing
- Phase-confirmed biallelic case data would be needed if a recessive disease context is being considered.
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Still missing
- A de novo report without full parentage confirmation would be needed.
PP1 No segregation data were identified showing that this variant tracks with disease in affected family members. Details ▾Hide ▴
Still missing
- Informative pedigree or family testing data would be needed.
PP4 No phenotype information was provided that is sufficiently specific to MSH3-related disease to apply PP4. Details ▾Hide ▴
Still missing
- Detailed clinical phenotype and any tumor or inheritance context would be needed.
PP5 A ClinVar classification is available, but no independently reviewable primary evidence was identified to support use of a source-only pathogenic criterion. Details ▾Hide ▴
Evidence considered
- ClinVar lists this variant as Likely benign
- not pathogenic.
Still missing
- Primary case-level or experimental evidence would be needed rather than a submitter assertion alone.
Sources
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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 reports 1 homozygote.
- gnomAD v4.1 reports 5 homozygotes.
Still missing
- Disease-specific penetrance
- age-related expressivity
- and confirmed unaffected homozygous individuals would be needed.
Sources
BS3 No well-established functional or RNA study showing no damaging effect of this specific variant was identified. Details ▾Hide ▴
Still missing
- A negative RNA or functional assay directly evaluating c.2436-13G>T would be needed.
BS4 No non-segregation data were identified showing that this variant fails to track with disease in informative families. Details ▾Hide ▴
Still missing
- Informative family studies showing lack of segregation would be needed.
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. Details ▾Hide ▴
Still missing
- Phase-confirmed genotype data would be needed.
BP5 No alternate molecular explanation was identified that would establish this variant as occurring in a case with an independent cause of disease. Details ▾Hide ▴
Still missing
- Case-level phenotype and genotype context would be needed.
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. Details ▾Hide ▴
Evidence considered
- ClinVar reports Likely benign with criteria provided
- single submitter review status.
Still missing
- Primary evidence underlying the benign assertion would be needed for independent evaluation.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
Evidence considered
- Variant consequence is intronic with protein consequence reported as p.?
PM1 N/APM1 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants. This variant is intronic, so PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 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. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 is a missense-gene mechanism criterion and is not applicable to this intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 is a missense-specific criterion and is not applicable to this intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is intronic, so BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is not applied because this variant is intronic rather than synonymous, and no separate conservation-based noncoding rule was provided here. Details ▾Hide ▴
Evidence considered
- The variant is intronic at c.2436-13 and SpliceAI does not predict a significant splice effect.
Sources
Identifiers
- Gene
- MSH3
- Transcript
- NM_002439.5
- Coding (HGVS c.)
- NM_002439.5:c.2436-13G>T
- Protein (HGVS p.)
- NP_002430.3:p.?
- GRCh38
- chr5:80787552 G>T
- GRCh37
- chr5:80083371 G>T
Gene diagram
Every interpreted variant in MSH3, mapped onto the exon structure of NM_002439.5. Select a row to find it on the plot.
MSH3NM_002439.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MSH3
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2,106 / 1,589,706 alleles
AF 0.00132 · 5 homozygotes · FAF 0.00164
gnomAD v2.1
222 / 282,746 alleles
AF 0.000785 · 1 homozygotes · FAF 0.00137
By genetic ancestry
gnomAD v4.1
AF 0.0013 · 2106 / 1,589,706 alleles · 5 hom · FAF 0.0016
| European (non-Finnish)1972 / 1,158,070 | 0.00175 hom |
| Remaining individuals64 / 61,670 | 0.001 |
| Admixed American29 / 59,934 | 0.00048 |
| Ashkenazi Jewish14 / 29,444 | 0.00048 |
| African/African American17 / 74,390 | 0.00023 |
| European (Finnish)8 / 63,950 | 0.00013 |
| South Asian2 / 90,610 | 2.2e-05 |
0 alternate alleles recorded in 3 other groups: Amish, East Asian, Middle Eastern.
gnomAD v2.1
AF 0.00079 · 222 / 282,746 alleles · 1 hom · FAF 0.0014
| European (non-Finnish)191 / 129,082 | 0.00151 hom |
| Ashkenazi Jewish6 / 10,368 | 0.00058 |
| Remaining individuals3 / 7,220 | 0.00042 |
| Admixed American13 / 35,420 | 0.00037 |
| African/African American6 / 24,966 | 0.00024 |
| European (Finnish)3 / 25,120 | 0.00012 |
0 alternate alleles recorded in 2 other groups: East Asian, South Asian.
Statements
gnomAD 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.
gnomAD 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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
BP4 was applied as supporting benign computational evidence against splice disruption.
Evidence considered
- SpliceAI max delta score 0.02 with low individual donor and acceptor delta scores.
Still missing
- No additional splice-function assay was available.
Sources
PP3 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. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect; that support was not present here.
Evidence considered
- SpliceAI DS_AG 0.01
- DS_AL 0.02
- DS_DG 0.00
- DS_DL 0.00
- max delta 0.02.
- REVEL not found.
- BayesDel not found.
Still missing
- Additional validated splice predictors or RNA data could further clarify the splicing effect.
Sources
BP7 N/ABP7 is not applied because this variant is intronic rather than synonymous, and no separate conservation-based noncoding rule was provided here. Details ▾Hide ▴
Evidence considered
- The variant is intronic at c.2436-13 and SpliceAI does not predict a significant splice effect.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2,106 / 1,589,706 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1569286/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-80083371-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-80787552-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002439.5%3Ac.2436…
- OncoKB ↗www.oncokb.org/gene/MSH3/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH3+c.2436-13G%3ET
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).