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MSH2c.198C>AUncertain significance
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Variant interpretation report

MSH2 c.198C>A, p.(Tyr66Ter)

NM_000251.3:c.198C>A NP_000242.1:p.(Tyr66Ter) View identifiers
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.

About MSH2

No gene-level summary was recorded for this case.

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
PVS1Very strong
PVS1 · very strong

Nonsense variant NM_000251.3:c.198C>A (p.Tyr66Ter) introduces a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the VCEP InSiGHT MSH2 v2.0.0 PVS1_VeryStrong rule. Loss of function is an established disease mechanism for MSH2 in Lynch syndrome as confirmed by the ClinGen InSiGHT CSPEC framework.

PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v4.1 (0/1,601,554 alleles, AF=0.00000%), satisfying the VCEP InSiGHT MSH2 v2.0.0 PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Also absent from gnomAD v2.1 and gnomAD-Canada v1.0.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions

6 Pathogenic.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 2 not met · 8 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1_VeryStrong is met: c.198C>A (p.Tyr66Ter) is a nonsense variant introducing a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the InSiGHT MSH2 v2.0.0 VCEP PVS1 rule for full-strength PVS1.

PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,601,554 alleles) and gnomAD v2.1, satisfying the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles).

Under the InSiGHT MSH2 v2.0.0 VCEP combination rules (Richards et al. 2015 framework), the combination of 1 Pathogenic Very Strong (PVS1) and 1 Pathogenic Supporting (PM2) does not satisfy any rule for Pathogenic or Likely Pathogenic classification. A minimum of 1 Very Strong + 2 Supporting, or 1 Very Strong + 1 Moderate would be required for Pathogenic or Likely Pathogenic, respectively. The variant is classified as Variant of Uncertain Significance (VUS) per the VCEP combination rule set.

This variant has been reported as Pathogenic by 6 clinical laboratories in ClinVar (VariationID: 645593). However, the VCEP does not recognize PP5/ClinVar consensus as an applicable criterion, and no expert panel classification has been issued for this variant.

No variant-specific functional (PS3/BS3), segregation (PP1/BS4), tumor phenotype (PP4/BP5), or de novo (PS2) data were identified for this variant in any reviewed source. Full-text publications retrieved for relevant PMIDs (24362816, 10946232, 11257106, 15528792, 23391514) did not contain accessible article content — all returned Sci-Hub landing page artifacts without variant-specific evidence.

Met · 2

PVS1 Very strongNonsense variant NM_000251.3:c.198C>A (p.Tyr66Ter) introduces a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the VCEP InSiGHT MSH2 v2.0.0 PVS1_VeryStrong rule. Loss of function is an established disease mechanism for MSH2 in Lynch syndrome as confirmed by the ClinGen InSiGHT CSPEC framework. Details ▾Hide ▴
Evidence considered
  • Nonsense variant at codon 66 (≤891) meets VCEP PVS1_VeryStrong threshold
  • MSH2 germline LoF established as disease mechanism per CSPEC PVS1 guidance
  • PVS1 decision tree for MMR genes confirms nonsense variants ≤ codon 891 qualify for full-strength PVS1
Sources
cspec ↗pvs1_variant_assessmentpvs1_gene_context
PM2 SupportingThe variant is absent from gnomAD v4.1 (0/1,601,554 alleles, AF=0.00000%), satisfying the VCEP InSiGHT MSH2 v2.0.0 PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0/1
  • 601
  • 554 alleles (AF=0.00000%)
  • gnomAD v2.1: absent
  • gnomAD-Canada v1.0: absent
  • VCEP PM2_Supporting threshold: <0.00002
Sources
gnomad_v4 ↗gnomad_v2 ↗cspec ↗

Not met · 2 · evaluated, threshold not reached

BA1 VCEP InSiGHT MSH2 v2.0.0 BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%). The variant is absent from gnomAD v4.1 (0/1,601,554 alleles), so BA1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00000%
  • well below BA1 threshold of ≥0.1%
Sources
gnomad_v4 ↗cspec ↗
BS1 VCEP InSiGHT MSH2 v2.0.0 BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%). The variant is absent from gnomAD v4.1 (0/1,601,554 alleles), so BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00000%
  • below BS1 threshold of ≥0.01%
Sources
gnomad_v4 ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PS2 de novo point system requires specific parent-offspring testing data, which has not been identified in any reviewed source. Details ▾Hide ▴
Still missing
  • No de novo observations identified in ClinVar
  • literature
  • or other sources
PS3 No variant-specific calibrated functional assay data available. The VCEP InSiGHT MSH2 v2.0.0 PS3 requires calibrated functional odds for pathogenicity > 2.08 from validated assays. While the VCEP functional assay spreadsheet catalogs calibrated assays (PMID:24362816, 30504929, etc.), none report functional data for p.Tyr66Ter specifically. As a nonsense variant, functional testing is typically not pursued since PVS1 already captures the expected null effect. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet confirms calibrated assays exist for MMR genes
  • No variant-specific functional data identified for p.Tyr66Ter
Still missing
  • No variant-specific functional assay data available
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PP1 requires combined Bayes Likelihood Ratio from pedigree analysis. No segregation studies were identified in any reviewed source. Details ▾Hide ▴
Still missing
  • No co-segregation or pedigree data available
PP4 No tumor phenotype data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PP4 requires MSI-H tumors or loss of MMR protein expression consistent with variant location. While PP4 was applied to some InSiGHT pilot variants, no MSI/IHC data specific to p.Tyr66Ter was identified in the evidence sources. Details ▾Hide ▴
Still missing
  • No MSI or IHC tumor data for patients carrying this variant
Sources
cspec ↗
BS2 No data available for co-occurrence in trans with a known pathogenic MSH2 variant. The VCEP InSiGHT MSH2 v2.0.0 BS2 requires confirmed trans phase with a P/LP variant in a patient with CRC after age 45 without CMMRD features. Details ▾Hide ▴
Still missing
  • No trans co-occurrence data available
BS3 No variant-specific functional data demonstrating proficient MMR function. The VCEP InSiGHT MSH2 v2.0.0 BS3 requires calibrated functional assays with functional odds for pathogenicity ≤0.48, or proficient function in validated assays. As a nonsense variant introducing a stop codon at position 66, a null effect is expected and functional rescue data would be needed to support BS3. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet catalogs validated MMR assays
  • No variant-specific functional data demonstrating proficiency identified
Still missing
  • No functional assay data demonstrating proficient MMR activity for p.Tyr66Ter
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No segregation data available. The VCEP InSiGHT MSH2 v2.0.0 BS4 requires lack of co-segregation with disease in pedigrees with combined Bayes Likelihood Ratio <0.48. Details ▾Hide ▴
Still missing
  • No segregation/pedigree data available
BP5 No tumor phenotype data available. The VCEP InSiGHT MSH2 v2.0.0 BP5 requires MSS tumors, no loss of MMR protein expression, or LS spectrum tumors with inconsistent protein loss. No tumor data was identified for this variant. Details ▾Hide ▴
Still missing
  • No MSS/IHC tumor data available
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a missense substitution encoding the same amino acid change with a different nucleotide change, or variants affecting the same non-canonical splice nucleotide. c.198C>A is a nonsense variant, not a missense or splice variant. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPVCEP InSiGHT MSH2 v2.0.0 lists PS4 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPVCEP InSiGHT MSH2 v2.0.0 lists PM1 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change was classified as P/LP. c.198C>A is a nonsense variant (p.Tyr66Ter), not a missense change. Details ▾Hide ▴
Sources
pm5_candidates
PM6 VCEPVCEP InSiGHT MSH2 v2.0.0 lists PM6 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPVCEP InSiGHT MSH2 v2.0.0 lists PP2 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PP3 N/AVCEP InSiGHT MSH2 v2.0.0 PP3 applies only to missense variants (HCI prior probability >0.68) or non-canonical splice variants (SpliceAI delta ≥0.2). c.198C>A is a nonsense variant; the HCI priors table contains only missense substitutions and the variant is not found in it. SpliceAI delta score is 0.00, indicating no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • HCI priors: variant not in missense-only lookup table
  • SpliceAI: max delta = 0.00 (no splice prediction)
Sources
cspec ↗spliceai ↗
PP5 VCEPVCEP InSiGHT MSH2 v2.0.0 lists PP5 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPVCEP InSiGHT MSH2 v2.0.0 lists BP1 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP2 VCEPVCEP InSiGHT MSH2 v2.0.0 lists BP2 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/AVCEP InSiGHT MSH2 v2.0.0 BP4 applies only to missense variants (HCI prior <0.11) or intronic/synonymous variants (SpliceAI delta ≤0.1). c.198C>A is a nonsense variant. The HCI priors table does not contain nonsense variants. Details ▾Hide ▴
Evidence considered
  • HCI priors: variant not in missense-only table
  • SpliceAI: not applicable for nonsense
Sources
cspec ↗
BP6 VCEPVCEP InSiGHT MSH2 v2.0.0 lists BP6 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/AVCEP InSiGHT MSH2 v2.0.0 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. c.198C>A is a nonsense variant. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/AThe VCEP InSiGHT MSH2 v2.0.0 does not include PS5 as an applicable criterion. PP5 (the analogous criterion in VCEP terminology) is explicitly listed as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
MSH2
Transcript
NM_000251.3
Coding (HGVS c.)
NM_000251.3:c.198C>A
Protein (HGVS p.)
NP_000242.1:p.(Tyr66Ter)
GRCh38
chr2:47403389 C>A
GRCh37
chr2:47630528 C>A
ClinVar
645593

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…
gnomAD v4.1 0 / 1,601,554 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,601,554 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1601554 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74900 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.080
Pangolin splice gain
0.220

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/AVCEP InSiGHT MSH2 v2.0.0 PP3 applies only to missense variants (HCI prior probability >0.68) or non-canonical splice variants (SpliceAI delta ≥0.2). c.198C>A is a nonsense variant; the HCI priors table contains only missense substitutions and the variant is not found in it. SpliceAI delta score is 0.00, indicating no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • HCI priors: variant not in missense-only lookup table
  • SpliceAI: max delta = 0.00 (no splice prediction)
Sources
cspec ↗spliceai ↗
BP4 N/AVCEP InSiGHT MSH2 v2.0.0 BP4 applies only to missense variants (HCI prior <0.11) or intronic/synonymous variants (SpliceAI delta ≤0.1). c.198C>A is a nonsense variant. The HCI priors table does not contain nonsense variants. Details ▾Hide ▴
Evidence considered
  • HCI priors: variant not in missense-only table
  • SpliceAI: not applicable for nonsense
Sources
cspec ↗
BP7 N/AVCEP InSiGHT MSH2 v2.0.0 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. c.198C>A is a nonsense variant. Details ▾Hide ▴
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
    Thompson BA et al. · 2014
    No paper-specific finding is recorded.
    PMID 24362816 ↗
  • Structure and function of mismatch repair proteins.
    No paper-specific finding is recorded.
    PMID 10946232 ↗
  • Deficient DNA mismatch repair: a common etiologic factor for colon cancer.
    No paper-specific finding is recorded.
    PMID 11257106 ↗
  • Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.
    No paper-specific finding is recorded.
    PMID 15528792 ↗
  • Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
    No paper-specific finding is recorded.
    PMID 23391514 ↗
  • Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis.
    No paper-specific finding is recorded.
    PMID 7726159 ↗
  • CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.
    No paper-specific finding is recorded.
    PMID 8566964 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,601,554 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 6 Pathogenic 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

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; MAF= 0.00000%, 0/1601554 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74900 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories). (ClinVarID = 645593)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.