About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.802dup, p.(Ser268PhefsTer16)
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 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1, so the observed population frequency is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength.
PVS1Very strong
PVS1 · very strong
This variant is a frameshift duplication predicted to cause p.(Ser268PhefsTer16), introducing a premature termination codon at codon 283. Under the MSH2 InSiGHT specification, nonsense or frameshift variants introducing a premature stop codon at or before codon 891 meet PVS1 at very strong strength, and this truncation is well upstream of that threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Applied the explicit InSiGHT/CSPEC final-classification framework from final_classification_framework.json (source: cspec_ruleset; Richards et al. 2015 combining rules as represented in the retrieved CSPEC ruleset), rather than generic ACMG fallback rules.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 2 not met · 7 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MSH2 c.802dup (p.(Ser268PhefsTer16)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by 1 clinical laboratory.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles).
The duplication causes a frameshift with a premature stop codon at p.(Ser268PhefsTer16), and this truncation is upstream of the MSH2 codon 891 cutoff for PVS1 Very Strong in the InSiGHT specification.
SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, indicating no additional splice effect is predicted beyond the truncating consequence of the duplication.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1, so the observed population frequency is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
Sources
PVS1 Very strongThis variant is a frameshift duplication predicted to cause p.(Ser268PhefsTer16), introducing a premature termination codon at codon 283. Under the MSH2 InSiGHT specification, nonsense or frameshift variants introducing a premature stop codon at or before codon 891 meet PVS1 at very strong strength, and this truncation is well upstream of that threshold. Details ▾Hide ▴
Rule
Nonsense/frameshift variant introducing premature termination codon <= codon 891 in MSH2.
Evidence considered
- Loss of function is an established disease mechanism for MSH2
- Variant type: frameshift
- Protein consequence: NP_000242.1:p.(Ser268PhefsTer16)
- Predicted stop codon position 283
- Variant is in exon 5
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentprefetchvcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___m_m_r
Not met · 2 · evaluated, threshold not reached
BS1 This variant is absent from gnomAD v4.1, so its filtering allele frequency is below the BS1 threshold of >=0.0001 and BS1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001, excluding founder pathogenic variants.
Evidence considered
- Absent from gnomAD v4.1
Sources
BA1 This variant is absent from gnomAD v4.1, so its filtering allele frequency is below the BA1 threshold of >=0.001 and BA1 is not met. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency >=0.001, excluding founder pathogenic variants.
Evidence considered
- Absent from gnomAD v4.1
Sources
Not assessed · 7 · no assessment recorded
PP4 No tumor microsatellite instability, mismatch repair immunohistochemistry, or phenotype data were identified to show that this variant is associated with a Lynch syndrome-specific clinical presentation under the MSH2 specification. Details ▾Hide ▴
Rule
1 CRC/endometrial MSI-H tumor and/or loss of MMR protein expression consistent with the variant location for supporting strength; stronger levels require additional independent tumors.
Still missing
- Tumor MSI results
- MMR IHC results
- Clinical phenotype or family history details
Sources
BS4 No segregation data or Bayes likelihood ratio were identified, so lack of co-segregation with disease cannot be evaluated. Details ▾Hide ▴
Rule
Lack of co-segregation with disease in pedigree(s) with a combined Bayes likelihood ratio <0.05 for strong or >0.05 and <=0.48 for supporting.
Still missing
- Segregation data
- Calculated Bayes likelihood ratio
Sources
PS2 No confirmed de novo data were identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
De novo points-based framework: >=4 very strong, 2-3.5 strong, 1-1.5 moderate, 0.5 supporting.
Still missing
- Parental testing
- De novo point calculation
Sources
PP1 No co-segregation data or Bayes likelihood ratio were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
Co-segregation with disease in pedigree(s) with a combined Bayes likelihood ratio >2.08 to <=4.3 for supporting, >4.3 to <=18.7 for moderate, and >18.7 in >=2 families for strong.
Still missing
- Segregation data
- Calculated Bayes likelihood ratio
Sources
BP5 No tumor profile data were identified to show multiple mismatch-repair-inconsistent tumors or MLH1-specific somatic findings that would argue against pathogenicity for an MSH2 variant. Details ▾Hide ▴
Rule
Mismatch-repair-inconsistent tumor evidence framework for supporting or strong benign evidence.
Still missing
- Tumor MSI results
- Tumor IHC results
- Tumor molecular profile
Sources
BS2 No phased in trans co-occurrence with a known pathogenic MSH2 variant and no phenotype data excluding CMMRD were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Co-occurrence in trans with a known pathogenic sequence variant in a patient whose phenotype argues against CMMRD.
Still missing
- Phase-confirmed co-occurrence data
- Clinical data relevant to CMMRD exclusion
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PM3 No phased in trans observations or points-based recessive evidence were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
Points-based in trans framework: 0.5 supporting, 1-1.5 moderate, 2-3.5 strong, >=4 very strong.
Still missing
- Phase-confirmed in trans observations
- PM3 point calculation
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
BP3 N/ABP3 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, whereas this variant is a frameshift duplication. Details ▾Hide ▴
BS3 N/AThe referenced MMR functional assay resources are directed to missense, splice-site, and synonymous variants, and no calibrated benign functional assay data were identified for this frameshift variant. Details ▾Hide ▴
Evidence considered
- Variant type: frameshift
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_tprefetch
PM5 N/APM5 applies to missense variants at the same amino acid residue, whereas this variant is a frameshift duplication. Details ▾Hide ▴
BP2 N/ABP2 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
BP4 N/ABP4 in the MSH2 specification applies to missense variants with a low HCI prior probability or to intronic/synonymous variants with SpliceAI <=0.1; this variant is a frameshift duplication. Details ▾Hide ▴
BP6 N/ABP6 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PS1 N/APS1 applies to the same amino acid change produced by a different nucleotide change or to certain non-canonical splice variants, which is not the mechanism for this frameshift duplication. Details ▾Hide ▴
PM1 N/APM1 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
cspec ↗vcep_m_m_r___f_u_n_c_t_i_o_n_a_l___d_o_m_a_i_n_s
PP5 N/APP5 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PM6 N/APM6 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PS4 N/APS4 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PM4 N/APM4 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PS3 N/AThe referenced MMR functional assay resources are directed to missense, splice-site, and synonymous variants, and no calibrated pathogenic functional assay data were identified for this frameshift variant. Details ▾Hide ▴
Evidence considered
- Variant type: frameshift
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_tprefetch
PP3 N/APP3 in the MSH2 specification applies to missense variants with an elevated HCI prior probability or to non-canonical splice variants with SpliceAI >=0.2; this variant is a frameshift duplication. Details ▾Hide ▴
BP1 N/ABP1 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
PP2 N/APP2 is not used in the MSH2 specification. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.802dup
- Protein (HGVS p.)
- NP_000242.1:p.(Ser268PhefsTer16)
- GRCh38
- chr2:47414275 G>GT
- GRCh37
- chr2:47641414 G>GT
Gene diagram
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.
MSH2NM_000251.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in MSH2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, whereas this variant is a frameshift duplication. Details ▾Hide ▴
BP4 N/ABP4 in the MSH2 specification applies to missense variants with a low HCI prior probability or to intronic/synonymous variants with SpliceAI <=0.1; this variant is a frameshift duplication. Details ▾Hide ▴
PP3 N/APP3 in the MSH2 specification applies to missense variants with an elevated HCI prior probability or to non-canonical splice variants with SpliceAI >=0.2; this variant is a frameshift duplication. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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
Captured gnomAD v4.1 source record
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 ↗
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/variation/1761732/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47641414-G-GT?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47414275-G-GT?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.802d…
- OncoKB ↗www.oncokb.org/gene/MSH2/S268Ffs*16
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.802dup
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.