About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.1381G>A, p.(Asp461Asn)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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 ClinGen MSH2 VCEP v2.0.0. 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD v4.1 at an allele frequency of 6.31e-07 (1/1,584,114 alleles; 0 homozygotes), well below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). It is absent from gnomAD v2.1.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
HCI prior probability for pathogenicity is 0.0014, well below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors concordantly suggest a benign effect: REVEL=0.296, BayesDel=-0.07, SpliceAI max delta=0.01 (no splicing impact).
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; maps to Uncertain Significance - Conflicting Evidence.
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
1 / 1,584,114 alleles
gnomAD v4.1: 1 / 1,584,114 alleles. Recorded AF 6.31268e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000251.2:c.1381G>A (p.Asp461Asn) is a missense variant in MSH2 exon 8. It is absent from ClinVar and extremely rare in gnomAD v4.1 (1/1,584,114 alleles; AF=6.31e-07), meeting PM2_Supporting under the InSiGHT MSH2 VCEP v2.0.0.
In silico predictions are concordantly benign: HCI prior probability is 0.0014 (<0.11 threshold), REVEL is 0.296, BayesDel is -0.07, and SpliceAI predicts no splicing impact (max delta=0.01). This meets BP4_Supporting under the VCEP framework.
No functional data, co-segregation data, tumor phenotype data, or de novo observations are available for this variant. No same-residue comparator variants classified as pathogenic by this VCEP were identified. PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP1, PP2, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP5, BP6, and BP7 are either not met or not applicable.
With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting), the evidence is insufficient to classify this variant. The variant is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MSH2 VCEP v2.0.0 combining rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is present in gnomAD v4.1 at an allele frequency of 6.31e-07 (1/1,584,114 alleles; 0 homozygotes), well below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). It is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=6.31e-07 (1/1
- 584
- 114 alleles)
- highest in East Asian (AF=2.24e-05
- 1/44
- 604). gnomAD v2.1: absent.
Sources
BP4 SupportingHCI prior probability for pathogenicity is 0.0014, well below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors concordantly suggest a benign effect: REVEL=0.296, BayesDel=-0.07, SpliceAI max delta=0.01 (no splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior=0.0014 (BP4_Supporting threshold: <0.11). REVEL=0.296. BayesDel=-0.07. SpliceAI max delta=0.01 (no splicing alteration).
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No different nucleotide change encoding the same amino acid substitution (p.Asp461Asn) has been previously classified as Pathogenic or Likely Pathogenic by this VCEP. The variant is absent from ClinVar and no PS1 comparator exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-amino-acid comparator identified in VCEP pilot variant spreadsheet.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
PS2 No de novo observations for this variant have been reported in the literature or clinical databases. Details ▾Hide ▴
Evidence considered
- No de novo data identified.
Still missing
- Absence of proband/parental phase data.
PS3 No functional assay data exists for NM_000251.2:c.1381G>A (p.Asp461Asn). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. The VCEP functional assay documentation spreadsheet does not list this variant among tested residues. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. VCEP functional assay spreadsheet contains no data for codon 461.
Still missing
- No calibrated functional assay data for this variant.
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
PM5 No different missense change at codon 461 has been classified as Pathogenic or Likely Pathogenic by this VCEP. The PM5 candidate search returned zero same-residue comparator variants. VCEP PM5 additionally requires PP3 to be supporting, which is not met (HCI prior=0.0014). Details ▾Hide ▴
Evidence considered
- Zero same-residue missense comparator variants identified
- PP3 not met.
Still missing
- No P/LP missense comparator at codon 461.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No pedigree or co-segregation data identified.
Still missing
- Family segregation data not available.
PP3 In silico predictions do not support a deleterious effect. HCI prior probability for pathogenicity is 0.0014, well below the VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.296 (not strongly pathogenic), BayesDel score is -0.07 (benign direction), and SpliceAI max delta is 0.01 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior=0.0014 (threshold for PP3_Supporting: >0.68). REVEL=0.296. BayesDel=-0.07. SpliceAI max delta=0.01.
Sources
PP4 No tumor data (MSI status, MMR immunohistochemistry) are available to assess whether the patient's phenotype is specific for Lynch syndrome. VCEP PP4 requires MSI-H tumor data and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor MSI/IHC data available.
Still missing
- Tumor MSI status and MMR IHC data not available.
Sources
BA1 gnomAD v4.1 allele frequency is 6.31e-07, far below the VCEP BA1 threshold of >=0.001 (>=0.1%). The variant is not a common polymorphism. Details ▾Hide ▴
BS1 gnomAD v4.1 allele frequency is 6.31e-07, far below the VCEP BS1 threshold of >=0.0001 (>=0.01%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=6.31e-07
- below BS1 threshold of >=0.0001.
Sources
BS2 No data on co-occurrence in trans with a known pathogenic MSH2 variant in an individual without CMMRD features. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available.
Still missing
- Trans phase data not available.
BS3 No functional data demonstrating normal or proficient MMR function for this variant. VCEP BS3 requires calibrated functional assays with functional odds for pathogenicity <=0.05, or variant-specific proficient function in MMR assays. No such data exist for p.Asp461Asn. Details ▾Hide ▴
Evidence considered
- No functional data showing proficient MMR function for this variant.
Still missing
- No functional assay data for this variant.
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Family segregation data not available.
BP5 No tumor data available to assess MSS status or MMR protein expression. VCEP BP5 requires observation of MSS tumors and/or retained MMR protein expression inconsistent with the gene harboring the variant. Details ▾Hide ▴
Evidence considered
- No tumor data available.
Still missing
- Tumor MSS status and MMR IHC data not available.
PS5 No different missense change at codon 461 has been established as pathogenic. PM5 candidate search returned zero same-residue comparators in ClinVar, and the VCEP pilot variant spreadsheet contains no classifications for codon 461. No evidence supports PS5. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified in ClinVar or VCEP pilot spreadsheet.
Still missing
- No pathogenic comparator at this codon.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution; VCEP PVS1 rules apply only to null variants (nonsense, frameshift, splice consensus, CNV) and not to missense changes. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPVCEP marks PS4 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
PM1 VCEPVCEP explicitly marks PM1 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
PM3 N/ATrans co-occurrence assessment not applicable in the absence of biallelic genotype data. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPProtein length change criterion not applicable to this missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPVCEP marks PM6 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
PP2 VCEPVCEP marks PP2 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
PP5 VCEPVCEP marks PP5 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
BP1 VCEPVCEP marks BP1 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
BP2 VCEPVCEP marks BP2 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
BP3 VCEPIn-frame deletion/insertion criterion not applicable to this missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPVCEP marks BP6 as Not Applicable for MSH2. Details ▾Hide ▴
Sources
BP7 N/ANon-synonymous missense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.2
- Coding (HGVS c.)
- NM_000251.2:c.1381G>A
- Protein (HGVS p.)
- NP_000242.1:p.(Asp461Asn)
- GRCh38
- chr2:47445652 G>A
- GRCh37
- chr2:47672791 G>A
Gene diagram
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.2. Select a row to find it on the plot.
MSH2NM_000251.2
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 MSH2
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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
1 / 1,584,114 alleles
AF 6.31e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.3e-07 · 1 / 1,584,114 alleles · 0 hom
| East Asian1 / 44,604 | 2.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.31268e-07; MAF= 0.00006%, 1/1584114 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.24195e-05; MAF= 0.00224%, 1/44604 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.296
- BayesDel
- -0.070
How the predictions were used
BP4 SupportingHCI prior probability for pathogenicity is 0.0014, well below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors concordantly suggest a benign effect: REVEL=0.296, BayesDel=-0.07, SpliceAI max delta=0.01 (no splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior=0.0014 (BP4_Supporting threshold: <0.11). REVEL=0.296. BayesDel=-0.07. SpliceAI max delta=0.01 (no splicing alteration).
Sources
PP3 In silico predictions do not support a deleterious effect. HCI prior probability for pathogenicity is 0.0014, well below the VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.296 (not strongly pathogenic), BayesDel score is -0.07 (benign direction), and SpliceAI max delta is 0.01 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- HCI prior=0.0014 (threshold for PP3_Supporting: >0.68). REVEL=0.296. BayesDel=-0.07. SpliceAI max delta=0.01.
Sources
BP7 N/ANon-synonymous missense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. Details ▾Hide ▴
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.296. BayesDel score = -0.0698272. HCI prior probability for pathogenicity = 0.0014. MAPP score = 2.8. Custom PP2 score = 0.069.
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
1 / 1,584,114 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1577628936
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000251.2%3Ac.1381G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47672791-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47445652-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47445652-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.2%3Ac.1381…
- OncoKB ↗www.oncokb.org/gene/MSH2/D461N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.1381G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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= 6.31268e-07; MAF= 0.00006%, 1/1584114 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.24195e-05; MAF= 0.00224%, 1/44604 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.296. BayesDel score = -0.0698272. HCI prior probability for pathogenicity = 0.0014. MAPP score = 2.8. Custom PP2 score = 0.069.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.