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MSH2c.23C>GNot classified
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Variant interpretation report

MSH2 c.23C>G, p.(Thr8Arg)

NM_000251.3:c.23C>G NP_000242.1:p.(Thr8Arg) Missense · exon 1 View identifiers
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.

About MSH2

MSH2 is a tumor suppressor gene that encodes a key protein in the DNA mismatch repair system, which finds and fixes errors made during DNA replication. The MSH2 protein pairs with MSH6 or MSH3 to form complexes that recognize mismatched base pairs and trigger their repair. Inherited mutations in MSH2 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), predisposing to colorectal, endometrial, ovarian, and other cancers, and biallelic mutations cause constitutional mismatch repair deficiency. Loss of MSH2 function increases the mutation rate and drives tumor development, particularly in colorectal and endometrial cancers, and mismatch-repair-deficient tumors respond particularly well to immune checkpoint inhibitor therapies.

NCBI Gene ↗ OncoKB ↗
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. 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

Met at Supporting: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP PM2 threshold of 0.00002.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met, supporting: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP BP4 threshold of <0.11.

Recorded classification: Not classified

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; 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.

No screenshot for this evidence
REVEL score
0.516 recorded score

Recorded REVEL score: 0.516. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
6 reported laboratory submissions

3 Uncertain significance · 1 Likely benign · 1 Uncertain Significance · 1 Benign.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

All three requested criteria are governed by the MSH2 InSiGHT VCEP framework; the variant is missense p.(Thr8Arg), PVS1 is outside the applicable loss-of-function classes, and PM4 and BP3 are explicitly Not Applicable.

The exact variant notations c.23C>G, p.Thr8Arg, and p.T8R were searched in both named governing full-text files; no exact entry was found.

For this criterion group, PS4, PP5, and BP6 are not applicable under the governing MSH2 InSiGHT VCEP rules.

PP4 and BP5 are applicable in principle but remain not assessed because the case lacks patient-specific tumor phenotype and alternate-molecular-basis data.

The exact variant was searched in both declared VCEP full-text files using c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.

Only PM3 and BP2 were adjudicated. The MSH2-specific VCEP specification governs both criteria.

PM3 cannot be assigned without documented affected-proband co-occurrence, a second pathogenic/likely pathogenic MSH2 variant, and phase or CMMRD clinical evidence; BP2 is explicitly not applicable.

Population evidence supports PM2 at Supporting strength under the governing MSH2 VCEP; BA1 and BS1 are not met because the gnomAD v4.1 Grpmax FAF is below both benign-frequency thresholds.

BS2 remains not assessed because the VCEP requires patient-level confirmed in-trans co-occurrence and clinical context not supplied by the population dataset.

Met · 2

PM2 SupportingMet at Supporting: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP PM2 threshold of 0.00002. Details ▾Hide ▴
Reasoning

The governing MSH2 InSiGHT VCEP Version 2.0 specifies PM2 at Supporting strength for an allele frequency below 0.00002 (less than 1 in 50,000 alleles) in gnomAD v4.1. This variant has total AF 1.87498e-06, gnomAD v4.1 Grpmax FAF 4.43e-06, and zero homozygotes, all satisfying the VCEP PM2 threshold. No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt; the governing VCEP rule directly determines this criterion.

Rule
MSH2 InSiGHT VCEP v2.0 PM2: Supporting when allele frequency is <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
Evidence considered
  • The governing MSH2 InSiGHT VCEP Version 2.0 defines PM2 at Supporting strength as allele frequency <0.00002 in gnomAD v4.
  • gnomAD v4.1 reports total AF 1.87498e-06, Grpmax FAF 4.43e-06, 3 of 1,600,016 alleles, and zero homozygotes.
  • The complete converted VCEP-pilot-variants---MMR.xlsx.txt was searched for c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr
BP4 SupportingMet, supporting: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP BP4 threshold of <0.11. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000251.3:c.23C>G (p.Thr8Arg/p.T8R), and the governing InSiGHT MSH2 VCEP specification provides a missense BP4 rule based on the HCI prior probability. The exact on-record HCI-PRIORS-MSH2 entry reports a pathogenicity probability of 0.0013, which is <0.11 and therefore directly satisfies BP4_Supporting. The REVEL score is 0.516 and does not independently meet the supplied generic BP4 Supporting threshold of <=0.29; it is not needed because the VCEP HCI rule is met. The available BayesDel score is not interpretable for ACMG strength because no generic calibration is established and the VCEP specifies no BayesDel cutoff.

Rule
Missense variant with HCI prior probability for pathogenicity <0.11 = BP4_Supporting, per the MSH2 InSiGHT VCEP specification.
Evidence considered
  • The MSH2 InSiGHT VCEP specification (version 2.0) defines BP4_Supporting for a missense variant with HCI prior probability <0.11.
  • The on-record HCI-PRIORS-MSH2 table contains the exact c.23C>G / p.T8R entry and reports pathogenicity probability 0.0013.
  • The local REVEL lookup reports 0.516, which is above the supplied generic BP4 Supporting threshold of <=0.29; this alternative path is not met but does not override the VCEP HCI rule.
  • The local BayesDel score is 0.0317561, but no generic ACMG strength calibration is established and the governing MSH2 VCEP provides no BayesDel cutoff, so it is not available for BP4 adjudication.
Sources
cspec ↗vcep_hci_priors_msh2revelbayesdel

Not met · 4 · evaluated, threshold not reached

PM5 Not met: no same-residue comparator was found, and HCI prior 0.0013 is below the VCEP PP3 supporting threshold of >0.68. Details ▾Hide ▴
Reasoning

The governing MSH2 VCEP PM5 rule requires a different missense change at the same residue classified by the VCEP as Pathogenic or Likely Pathogenic, and it permits PM5 only when PP3 supporting is met. No same-residue comparator was found in pm5_candidates.json, and the exact HCI prior is 0.0013, which is below the VCEP PP3 supporting threshold (>0.68) and instead meets the VCEP BP4 supporting threshold (<0.11). PM5 is therefore not met.

Rule
Use PM5 only for a different missense change at the same residue classified by this VCEP as Pathogenic or Likely Pathogenic, and only if PP3 supporting is met.
Evidence considered
  • The MSH2 VCEP PM5 rule requires a different same-residue missense variant classified by the VCEP as Pathogenic or Likely Pathogenic and requires PP3 supporting for the assessed variant.
  • pm5_candidates.json reports zero same-residue candidates, zero expert-panel pathogenic/likely pathogenic candidates, and zero non-expert majority pathogenic/likely pathogenic candidates.
  • The exact HCI prior for c.23C>G / p.T8R is 0.0013; the MSH2 VCEP assigns PP3 supporting only above 0.68 and BP4 supporting below 0.11.
Still missing
  • pm5_candidates.json reports zero same-residue comparator candidates; candidate harvesting also recorded an HTTP 429 error, so no comparator could be independently adjudicated from that collection.
  • The HCI prior table's exact c.23C>G entry is supportive of BP4, not PP3.
Sources
cspec ↗pm5_candidateshci_priorvcep_hci_priors_msh2
PP3 Not met: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP PP3 Supporting threshold of >0.68, and REVEL 0.516 is below 0.644. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000251.3:c.23C>G (p.Thr8Arg/p.T8R), so the MSH2 missense computational path applies. The governing InSiGHT MSH2 VCEP specification assigns PP3_Moderate only when the HCI prior probability is >0.81 and PP3_Supporting when it is >0.68 and <=0.81. The exact HCI lookup entry for c.23C>G reports a pathogenicity probability of 0.0013, which does not meet either VCEP PP3 threshold. The available REVEL score is 0.516, below the supplied generic PP3 Supporting threshold of >=0.644 from ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG strength calibration is established and the MSH2 VCEP does not specify a BayesDel cutoff.

Rule
Missense variant with HCI prior probability for pathogenicity >0.81 = PP3_Moderate; >0.68 and <=0.81 = PP3_Supporting, per the MSH2 InSiGHT VCEP specification.
Evidence considered
  • The MSH2 InSiGHT VCEP specification (version 2.0) governs PP3 and defines PP3_Moderate for missense variants with HCI prior probability >0.81 and PP3_Supporting for >0.68 and <=0.81.
  • The on-record HCI-PRIORS-MSH2 table contains the exact c.23C>G / p.T8R entry and reports pathogenicity probability 0.0013.
  • The local REVEL lookup reports 0.516; the supplied ClinGen SVI calibration threshold for PP3 Supporting is >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The local BayesDel score is 0.0317561, but no generic ACMG strength calibration is established and the governing MSH2 VCEP provides no BayesDel cutoff, so it is not available for PP3 adjudication.
Sources
cspec ↗vcep_hci_priors_msh2revelbayesdel
BA1 Not met: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The governing MSH2 InSiGHT VCEP Version 2.0 specifies BA1 when the gnomAD v4 Grpmax filtering allele frequency is at least 0.001 (0.1%) and the variant is not a founder pathogenic variant. This variant's gnomAD v4.1 Grpmax FAF is 4.43e-06, with total AF 1.87498e-06 (3/1,600,016 alleles), so it is far below the BA1 threshold. No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt; that file is a precedent table and does not alter the directly applicable VCEP threshold.

Rule
MSH2 InSiGHT VCEP v2.0 BA1: gnomAD v4 Grpmax filtering allele frequency >=0.001 (0.1%) and variant excluded as a founder pathogenic variant.
Evidence considered
  • The governing MSH2 InSiGHT VCEP Version 2.0 defines BA1 as gnomAD v4 Grpmax filtering allele frequency >=0.001 (0.1%), excluding founder pathogenic variants.
  • gnomAD v4.1 reports Grpmax FAF 4.43e-06, total AF 1.87498e-06, 3 of 1,600,016 alleles, and zero homozygotes.
  • The complete converted VCEP-pilot-variants---MMR.xlsx.txt was searched for c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr
BS1 Not met: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP BS1 lower threshold of 0.0001. Details ▾Hide ▴
Reasoning

The governing MSH2 InSiGHT VCEP Version 2.0 specifies BS1 when the gnomAD v4 Grpmax filtering allele frequency is at least 0.0001 and below 0.001 (0.01-0.1%) and the variant is excluded as a founder pathogenic variant. The observed gnomAD v4.1 Grpmax FAF is 4.43e-06, below 0.0001; the highest population AF is 2.66937e-05 in the African/African American population, also below the BS1 lower bound. No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.

Rule
MSH2 InSiGHT VCEP v2.0 BS1: gnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001 (0.01-0.1%) and variant excluded as a founder pathogenic variant.
Evidence considered
  • The governing MSH2 InSiGHT VCEP Version 2.0 defines BS1 as gnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001 (0.01-0.1%), excluding founder pathogenic variants.
  • gnomAD v4.1 reports Grpmax FAF 4.43e-06 and the highest observed population AF 2.66937e-05 in the African/African American population, both below 0.0001.
  • The complete converted VCEP-pilot-variants---MMR.xlsx.txt was searched for c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr

Not assessed · 10 · no assessment recorded

PS1 Not assessed: no VCEP-established pathogenic alternative nucleotide encoding p.Thr8Arg was identified in the reviewed evidence. Details ▾Hide ▴
Reasoning

The governing MSH2 VCEP PS1 rule requires a different nucleotide change encoding the same amino-acid substitution, previously established by that VCEP as Pathogenic, with no splice defect. The reviewed case evidence and PM5 candidate collection provide no such p.Thr8Arg/p.T8R comparator; therefore PS1 cannot be assigned. The exact variant was found in the on-record HCI prior table, but that entry is not evidence for PS1.

Rule
A predicted missense substitution encoding the same amino-acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic, and not a predicted or confirmed splice defect.
Evidence considered
  • The MSH2 VCEP PS1 rule requires the same amino-acid change from a different underlying nucleotide change and prior VCEP Pathogenic classification.
  • The PM5 candidate collection reported zero same-residue candidates and zero expert-panel or non-expert majority pathogenic/likely pathogenic candidates; it cannot establish PS1.
  • The on-record HCI prior table contains the exact variant c.23C>G / p.T8R, but an exact-variant prior entry does not satisfy the PS1 comparator requirement.
Still missing
  • No VCEP-established Pathogenic alternative-nucleotide p.Thr8Arg comparator was available in the reviewed case evidence.
Sources
cspec ↗pm5_candidates
PS2 Not assessed: no documented proband, parental confirmation, de novo observation, Lynch-spectrum tumor, or de novo point total is available for applying the MSH2 PS2 thresholds. Details ▾Hide ▴
Reasoning

The governing InSiGHT MSH2 specification assigns PS2 according to de novo points: 2 points per proband when both maternity and paternity are confirmed and the proband has an MMR-deficient Lynch-spectrum tumor; 1 point when both parents are confirmed without tumor MSI/IHC/methylation data; or 0.5 points when de novo status is assumed and one or both parents are unconfirmed. The available case evidence does not document a proband, parental genotyping, maternity or paternity confirmation, a de novo observation, tumor type, tumor MSI/IHC/methylation findings, or a de novo point total, so PS2 cannot be assigned.

Rule
InSiGHT MSH2 PS2: >=4 de novo points = Very Strong; 2-3.5 = Strong; 1-1.5 = Moderate; 0.5 = Supporting.
Evidence considered
  • The MSH2 InSiGHT Version 2.0 specification requires 2, 1, or 0.5 de novo points per qualifying proband depending on parental confirmation and tumor data.
  • No case-level parental testing, de novo status, proband phenotype, qualifying tumor, or tumor MSI/IHC/methylation result is documented in the reviewed case evidence.
Still missing
  • Document the proband and phenotype, including a qualifying Lynch-spectrum tumor.
  • Provide variant testing results for the proband and both parents, including maternity and paternity confirmation.
  • Provide tumor MSI, MMR IHC, and MLH1 methylation results when available.
  • Calculate the applicable de novo points under the MSH2 InSiGHT specification.
Sources
cspec ↗
PS3 Not assessed: the calibrated assay defines abnormal MSH2 function as LOF score >0.4, but no variant-specific LOF score is reported for p.(Thr8Arg). Details ▾Hide ▴
Reasoning

The MSH2 VCEP specifies PS3 from calibrated functional assays with functional odds for pathogenicity >18.7 (strong), >4.3 and <=18.7 (moderate), or >2.08 and <=4.3 (supporting), with MMR function defect by the flowchart also qualifying at moderate strength. The VCEP assay documentation identifies the Jia et al. MSH2 deep-mutational-scanning assay (PMID:33357406) as approved and calibrated, with LOF score <=0 as normal and >0.4 as abnormal, validated with 22 pathogenic/likely pathogenic and 26 benign/likely benign controls. The case paper extraction and direct full-text search do not provide a variant-specific LOF score or an explicit c.23C>G/p.(Thr8Arg)/p.(T8R) result; the reported assay-wide tolerance and N-terminal-domain context cannot be assigned to this variant without that measurement. Therefore PS3 cannot be assessed.

Rule
Calibrated functional assays with functional odds for pathogenicity > 18.7; moderate at >4.3 and <= 18.7 or MMR function defect following the functional assay flowchart; supporting at >2.08 and <= 4.3.
Evidence considered
  • The MSH2 VCEP PS3 rule assigns strong evidence at functional odds for pathogenicity >18.7, moderate evidence at >4.3 and <=18.7 or by an MMR function defect following the flowchart, and supporting evidence at >2.08 and <=4.3.
  • The SVI assay table lists PMID:33357406 as an approved calibrated MSH2 assay with LOF score <=0 normal, LOF score >0.4 abnormal, 22 pathogenic/likely pathogenic validation controls, and 26 benign/likely benign validation controls.
  • PMID:33357406 reports a massively parallel MSH2 functional assay in MSH2-knockout HAP1 cells using 6-thioguanine selection, but its extracted finding and direct full-text notation search do not identify c.23C>G, p.(Thr8Arg), or p.(T8R), nor provide a variant-specific score.
Still missing
  • Functional-assay-SVI-documentation-MMR.xlsx was searched for c.23C>G, p.Thr8Arg, and p.T8R; no variant-specific entry was found.
  • Functional-assay-flowchart.pdf was searched for c.23C>G, p.Thr8Arg, and p.T8R; no variant-specific entry was found.
  • A variant-specific LOF score or calibrated functional-odds result for MSH2 c.23C>G (p.(Thr8Arg)/p.(T8R)) is required to assign PS3 strength.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:33357406 ↗
PM3 Not assessed: no affected-proband co-occurrence, second pathogenic MSH2 variant, phase result, or CMMRD feature assessment is documented for PM3 point assignment. Details ▾Hide ▴
Reasoning

The applicable InSiGHT MSH2 Version 2.0 specification applies PM3 to co-occurrence of the candidate variant with a known pathogenic or likely pathogenic variant in the same gene in a patient with clinical features consistent with constitutional mismatch repair deficiency (CMMRD). It assigns 1.0 point for a confirmed in-trans pathogenic/likely pathogenic variant and 0.5 points when phase is unknown, with PM3_Supporting at 0.5 points, PM3_Moderate at 1–1.5 points, PM3_Strong at 2–3.5 points, and PM3_Very Strong at ≥4 points. The available case evidence contains no affected-proband observation, second pathogenic/likely pathogenic MSH2 variant, phase result, or CMMRD clinical feature assessment for NM_000251.3:c.23C>G; therefore no PM3 points can be assigned.

Rule
Co-occurrence with a known pathogenic/likely pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD; pathogenic/likely pathogenic in trans = 1.0 point; phase unknown = 0.5 points; PM3 Supporting = 0.5 points, Moderate = 1–1.5 points, Strong = 2–3.5 points, Very Strong = ≥4 points.
Evidence considered
  • The InSiGHT MSH2 Version 2.0 specification requires same-gene pathogenic/likely pathogenic co-occurrence in a patient with CMMRD-consistent clinical features; confirmed in-trans phase contributes 1.0 point and unknown phase contributes 0.5 points.
  • The specification assigns PM3_Supporting at 0.5 points, PM3_Moderate at 1–1.5 points, PM3_Strong at 2–3.5 points, and PM3_Very Strong at ≥4 points.
  • The case evidence provides no affected-proband co-occurrence, second pathogenic/likely pathogenic MSH2 variant, phase information, or CMMRD feature assessment for this variant.
Still missing
  • Affected-proband case data with a second pathogenic or likely pathogenic MSH2 variant are not documented.
  • Phase testing establishing the variants in trans or cis is not documented.
  • Clinical features sufficient to assess CMMRD under the MSH2 specification are not documented.
Sources
cspec ↗
PP1 Not assessed: no pedigree data or combined segregation Bayes likelihood ratio is documented, leaving the PP1 Supporting threshold of >2.08 unevaluable. Details ▾Hide ▴
Reasoning

The governing InSiGHT MSH2 specification requires a combined segregation Bayes likelihood ratio greater than 2.08 and up to 4.3 for PP1 Supporting, greater than 4.3 and up to 18.7 for PP1 Moderate, or greater than 18.7 in at least two families for PP1 Strong. The available case evidence contains no pedigree, affected or unaffected relative genotypes, phenotype assessments, meioses, family count, or calculated segregation Bayes likelihood ratio, so PP1 cannot be assigned.

Rule
InSiGHT MSH2 PP1: combined Bayes likelihood ratio >2.08 and <=4.3 = Supporting; >4.3 and <=18.7 = Moderate; >18.7 in >=2 families = Strong.
Evidence considered
  • The MSH2 InSiGHT Version 2.0 specification sets PP1 thresholds at combined segregation Bayes likelihood ratios >2.08 to <=4.3 for Supporting, >4.3 to <=18.7 for Moderate, and >18.7 in at least two families for Strong.
  • No family pedigree, segregation genotypes, informative meioses, phenotype segregation data, or Bayes likelihood ratio is documented in the reviewed case evidence.
Still missing
  • Provide a pedigree identifying affected and unaffected relatives and their phenotypes.
  • Provide variant testing results for informative relatives and the number of informative meioses.
  • Provide family-level and combined segregation Bayes likelihood ratios, including the model assumptions used.
Sources
cspec ↗
PP4 Not assessed: no patient-specific MSI, IHC, tumor-genome, or CMMRD score is available to meet the VCEP PP4 thresholds. Details ▾Hide ▴
Reasoning

PP4 is applicable under the MSH2 InSiGHT VCEP specification, with supporting evidence requiring 1 CRC/Endometrial MSI-H tumor using the specified MSI panel or tumor genome and/or loss of MMR protein expression consistent with the variant location; moderate requires 2 independent tumors and strong requires at least 3 independent tumors in at least 2 families. The available case evidence contains no patient-specific tumor MSI/IHC results, tumor genome result, or CMMRD clinical scoring data, so PP4 cannot be assigned. The exact variant was not listed in VCEP-pilot-variants---MMR.xlsx.txt or Table-for-CMMRD-diagnosis.pdf.txt when searched as c.23C>G, p.Thr8Arg, and p.T8R; the latter is a general scoring table rather than a variant precedent table.

Rule
Supporting: 1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers or tumor genome and/or loss of MMR protein expression consistent with the variant location; Moderate: 2 independent tumors; Strong: >=3 independent tumors in >=2 families.
Evidence considered
  • The MSH2 InSiGHT VCEP defines PP4 Supporting as 1 CRC/Endometrial MSI-H tumor with a standard panel or tumor genome and/or MMR protein loss consistent with MSH2; Moderate requires 2 independent tumors and Strong requires at least 3 independent tumors in at least 2 families.
  • The CMMRD scoring table states that at least 3 points indicate CMMRD features, but no patient-specific clinical features or score are available for this case.
  • The exact variant was searched in the two declared PP4 VCEP full-text files under c.23C>G, p.Thr8Arg, and p.T8R without an exact entry.
Still missing
  • No patient-specific CRC/Endometrial MSI-H tumor result, tumor genome result, or MSH2-consistent MMR protein loss was available.
  • No patient-specific CMMRD score was available using Table-for-CMMRD-diagnosis.pdf.txt; the exact variant was not found there under c.23C>G, p.Thr8Arg, or p.T8R.
  • The exact variant was not found in VCEP-pilot-variants---MMR.xlsx.txt under c.23C>G, p.Thr8Arg, or p.T8R.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosisvcep_vcep_pilot_variants_mmr
BS2 Not assessed: gnomAD v4.1 has zero homozygotes, but VCEP BS2 requires confirmed in-trans patient co-occurrence and clinical-age evidence. Details ▾Hide ▴
Reasoning

The governing MSH2 InSiGHT VCEP Version 2.0 limits BS2 to a confirmed in-trans co-occurrence with a known pathogenic variant in the same gene in a patient with colorectal cancer after age 45 or another Lynch-spectrum cancer above its median age of onset, without clinical manifestations of constitutional mismatch repair deficiency. The available population data show zero gnomAD v4.1 homozygotes, but this does not establish the VCEP's required patient-level phase, cancer-age, or CMMRD criteria. No qualifying co-occurrence evidence was identified in the consolidated population evidence.

Rule
MSH2 InSiGHT VCEP v2.0 BS2: confirmed in-trans co-occurrence with a known pathogenic same-gene variant in a qualifying cancer patient older than the specified age threshold, without CMMRD manifestations.
Evidence considered
  • The governing MSH2 InSiGHT VCEP Version 2.0 requires confirmed in-trans co-occurrence with a known pathogenic same-gene variant, qualifying cancer age, and no CMMRD manifestations for BS2.
  • gnomAD v4.1 reports zero homozygotes, but a population homozygote count alone does not satisfy the VCEP BS2 rule.
  • The complete converted VCEP-pilot-variants---MMR.xlsx.txt was searched for c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.
Still missing
  • No patient-level confirmed in-trans co-occurrence with a known pathogenic MSH2 variant, qualifying cancer age, and absence of CMMRD manifestations was available.
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr
BS3 Not assessed: the calibrated assay defines normal MSH2 function as LOF score <=0, but no variant-specific LOF score is reported for p.(Thr8Arg). Details ▾Hide ▴
Reasoning

The MSH2 VCEP specifies BS3 from calibrated functional assays with functional odds for pathogenicity <=0.05 (strong) or >0.05 and <=0.48 (supporting), or from variant-specific proficient protein and mRNA assays following the MMR functional assay flowchart. The VCEP assay documentation identifies the Jia et al. MSH2 deep-mutational-scanning assay (PMID:33357406) as approved and calibrated, with LOF score <=0 as normal and >0.4 as abnormal, validated with 22 pathogenic/likely pathogenic and 26 benign/likely benign controls. The case paper extraction and direct full-text search do not provide a variant-specific LOF score or an explicit c.23C>G/p.(Thr8Arg)/p.(T8R) result; assay-wide tolerance and domain-level observations are insufficient for variant-specific proficient-function evidence. Therefore BS3 cannot be assessed.

Rule
Calibrated functional assays with functional odds for pathogenicity <= 0.05; supporting at >0.05 and <= 0.48; alternatively, variant-specific proficient function in protein and mRNA-based assays according to the MMR functional assay flowchart.
Evidence considered
  • The MSH2 VCEP BS3 rule assigns strong evidence at functional odds for pathogenicity <=0.05 and supporting evidence at >0.05 and <=0.48; variant-specific proficient protein and mRNA assays may support BS3 under the flowchart.
  • The SVI assay table lists PMID:33357406 as an approved calibrated MSH2 assay with LOF score <=0 normal, LOF score >0.4 abnormal, 22 pathogenic/likely pathogenic validation controls, and 26 benign/likely benign validation controls.
  • PMID:33357406 reports a massively parallel MSH2 functional assay in MSH2-knockout HAP1 cells using 6-thioguanine selection, but its extracted finding and direct full-text notation search do not identify c.23C>G, p.(Thr8Arg), or p.(T8R), nor provide a variant-specific score.
Still missing
  • Functional-assay-SVI-documentation-MMR.xlsx was searched for c.23C>G, p.Thr8Arg, and p.T8R; no variant-specific entry was found.
  • Functional-assay-flowchart.pdf was searched for c.23C>G, p.Thr8Arg, and p.T8R; no variant-specific entry was found.
  • A variant-specific LOF score or calibrated functional-odds result for MSH2 c.23C>G (p.(Thr8Arg)/p.(T8R)) is required to assign BS3 strength.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:33357406 ↗
BS4 Not assessed: no documented non-segregating relatives or combined segregation Bayes likelihood ratio is available to evaluate the BS4 Strong cutoff of <0.05. Details ▾Hide ▴
Reasoning

The governing InSiGHT MSH2 specification requires a combined segregation Bayes likelihood ratio below 0.05 for BS4 Strong or greater than 0.05 and up to 0.48 for BS4 Supporting, while accounting for phenocopies and other pathogenic variants that can confound apparent non-segregation. The available case evidence contains no pedigree, affected-relative genotypes, phenotype information, non-segregating observations, family count, or calculated Bayes likelihood ratio, so BS4 cannot be assigned.

Rule
InSiGHT MSH2 BS4: combined Bayes likelihood ratio <0.05 = Strong; >0.05 and <=0.48 = Supporting.
Evidence considered
  • The MSH2 InSiGHT Version 2.0 specification sets BS4 Strong at a combined non-segregation Bayes likelihood ratio <0.05 and BS4 Supporting at >0.05 to <=0.48.
  • No family pedigree, affected-relative testing, phenotype assessment, non-segregating observation, or Bayes likelihood ratio is documented in the reviewed case evidence.
Still missing
  • Provide a pedigree identifying affected relatives and their disease phenotypes.
  • Provide variant testing results for affected and unaffected relatives and informative meioses.
  • Document possible phenocopies or alternate pathogenic variants in the family.
  • Provide family-level and combined non-segregation Bayes likelihood ratios, including model assumptions.
Sources
cspec ↗
BP5 Not assessed: no qualifying MSS, MMR-IHC discordant, BRAF V600E, or MLH1-methylation tumor evidence is documented. Details ▾Hide ▴
Reasoning

BP5 is applicable under the MSH2 InSiGHT VCEP, but no patient-specific alternate molecular basis or tumor phenotype is documented. The VCEP requires 2 or 3 qualifying tumors for Supporting or at least 4 qualifying tumors for Strong, defined as CRC/Endometrial tumors with MSS and/or no MMR protein loss, inconsistent MMR protein loss in an LS-spectrum tumor, or the specified BRAF V600E/MLH1 methylation findings. None of these findings is available, so BP5 cannot be assigned.

Rule
Supporting: 2 or 3 tumors with MSS and/or no MMR protein loss or inconsistent MMR protein loss, or 1 BRAF V600E/MLH1 methylation finding; Strong: >=4 tumors or >=2 BRAF V600E/MLH1 methylation findings.
Evidence considered
  • The MSH2 InSiGHT VCEP defines BP5 Supporting as 2 or 3 qualifying tumors or 1 qualifying BRAF V600E/MLH1-methylation finding, and BP5 Strong as at least 4 qualifying tumors or at least 2 such BRAF V600E/MLH1-methylation findings.
  • No patient-specific alternate molecular basis or qualifying tumor result is documented.
Still missing
  • No patient-specific tumor count or tumor pathology results were available to evaluate the VCEP BP5 Supporting or Strong rules.
Sources
cspec ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.23C>G produces missense p.(Thr8Arg), not an MSH2 loss-of-function variant eligible for the VCEP PVS1 rule. Details ▾Hide ▴
Reasoning

The variant is NM_000251.3:c.23C>G, NP_000242.1:p.(Thr8Arg), an exonic missense substitution rather than a nonsense, frameshift, canonical splice, large genomic alteration, or confirmed aberrant-splicing variant. The MSH2 InSiGHT VCEP specification limits PVS1 to those loss-of-function classes, so PVS1 is not applicable; no PVS1 downgrade tier is relevant. The governing PVS1_DecisionTree_MMR.pdf and VCEP-pilot-variants---MMR.xlsx were searched for c.23C>G, p.Thr8Arg, and p.T8R, with no exact entry found.

Rule
MSH2 InSiGHT VCEP v2.0 PVS1 applicability rule
Evidence considered
  • The MSH2 InSiGHT VCEP specification lists PVS1 for nonsense/frameshift variants introducing a premature termination codon at or before codon 891, large genomic alterations, qualifying canonical splice variants, or confirmed aberrant splicing; this variant is missense p.(Thr8Arg).
  • The case normalization identifies NM_000251.3:c.23C>G as NP_000242.1:p.(Thr8Arg) / p.(T8R) with consequence class missense.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in PVS1_DecisionTree_MMR.pdf.txt.
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗
PS4 VCEPNot applicable: the MSH2 InSiGHT VCEP explicitly excludes PS4 proband-counting evidence for MMR variant classification. Details ▾Hide ▴
Reasoning

The MSH2 InSiGHT VCEP specification explicitly marks PS4 as not applicable and states that PS4 has not been utilized for MMR variant classification using proband counting because tumor IHC data are available for classification under PP4. No PS4 evidence is therefore assigned.

VCEP rule
Due to the availability of tumor IHC data for variant classification (see PP4), PS4 has not been utilized for MMR variant classification using proband counting.
Evidence considered
  • The MSH2 InSiGHT VCEP rule lists PS4 applicability as Not Applicable and states that PS4 has not been utilized for MMR variant classification using proband counting.
Sources
cspec ↗
PM1 VCEPNot applicable: the MSH2 VCEP marks PM1 Not Applicable, and its authoritative domain_tables list is empty. Details ▾Hide ▴
Reasoning

The governing MSH2 VCEP explicitly marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables key is present but empty, so there is no approved MSH2 critical-domain entry to apply. The required on-record MMR-Functional-domains.pdf.txt was searched and contains only the schematic description, with no c.23C>G, p.Thr8Arg, or p.T8R entry.

VCEP rule
Not Applicable according to the governing MSH2 VCEP.
Evidence considered
  • The MSH2 VCEP criteria specify PM1 as Not Applicable.
  • The authoritative vcep_materials.json domain_tables key is empty.
  • The on-record MMR-Functional-domains.pdf.txt was searched for all supplied variant notations and contained no variant-specific entry.
Still missing
  • MMR-Functional-domains.pdf.txt was searched for c.23C>G, p.Thr8Arg, and p.T8R; no variant entry was found.
  • vcep_materials.json has no approved MSH2 domain_tables entries.
Sources
cspec ↗vcep_mmr_functional_domainsPMID:33357406 ↗
PM4 VCEPNot applicable: the MSH2 VCEP explicitly designates PM4 as Not Applicable, and p.(Thr8Arg) causes no protein-length change. Details ▾Hide ▴
Reasoning

The MSH2 InSiGHT VCEP specification explicitly designates PM4 as Not Applicable. This variant is a single-residue missense substitution, p.(Thr8Arg), with no protein-length change or in-frame deletion/insertion consequence that would independently support PM4. The VCEP-pilot-variants---MMR.xlsx was searched for c.23C>G, p.Thr8Arg, and p.T8R, with no exact entry found.

VCEP rule
MSH2 InSiGHT VCEP v2.0 PM4 applicability: Not Applicable
Evidence considered
  • The MSH2 InSiGHT VCEP specification explicitly marks PM4 as Not Applicable.
  • The case normalization identifies the consequence as missense p.(Thr8Arg), a one-amino-acid substitution without a protein-length change.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗
PM6 VCEPNot applicable: the governing InSiGHT MSH2 specification designates PM6 as not applicable and routes assumed de novo evidence through PS2. Details ▾Hide ▴
Reasoning

The governing InSiGHT MSH2 Version 2.0 specification designates PM6 as not applicable. Its de novo framework is handled through PS2 point-based categories, including the 0.5-point category for assumed de novo status without confirmed maternity and/or paternity.

VCEP rule
InSiGHT MSH2 PM6: Not applicable; use the PS2 de novo point framework instead.
Evidence considered
  • The MSH2 InSiGHT Version 2.0 specification lists PM6 as not applicable.
  • The same specification states that assumed de novo observations without confirmed maternity and/or paternity are evaluated under PS2 at 0.5 points per qualifying proband.
Sources
cspec ↗
PP2 VCEPNot applicable: the governing MSH2 VCEP explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing MSH2 VCEP explicitly marks PP2 as Not Applicable. No generic gene-level missense-mechanism evidence can override that gene-specific specification.

VCEP rule
Not Applicable according to the governing MSH2 VCEP.
Evidence considered
  • The MSH2 VCEP criteria specify PP2 as Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: PP5 is excluded by the VCEP and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The MSH2 InSiGHT VCEP explicitly marks PP5 as not applicable. Independently, the exact ClinVar record has zero expert-panel submissions; its reported Likely benign assertion is from Ambry Genetics as a single submitter, while the remaining assertions are ordinary laboratory submissions. No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification exists to trigger PP5.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The MSH2 InSiGHT VCEP marks PP5 as Not Applicable for this VCEP.
  • The exact ClinVar record reports zero expert-panel submissions; all six submissions are single-submitter laboratory assertions, with classifications of uncertain significance, likely benign, and benign.
Sources
cspec ↗clinvar ↗
BP1 VCEPNot applicable: the governing MSH2 VCEP explicitly marks BP1 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing MSH2 VCEP explicitly marks BP1 as Not Applicable. The variant is missense, but generic BP1 reasoning cannot be applied where the gene-specific VCEP specification excludes the criterion.

VCEP rule
Not Applicable according to the governing MSH2 VCEP.
Evidence considered
  • The MSH2 VCEP criteria specify BP1 as Not Applicable.
Sources
cspec ↗
BP2 VCEPNot applicable: the InSiGHT MSH2 Version 2.0 specification explicitly designates BP2 as not applicable. Details ▾Hide ▴
Reasoning

The applicable InSiGHT MSH2 Version 2.0 specification explicitly designates BP2 as not applicable. Accordingly, BP2 is not evaluated for this MSH2 variant, regardless of whether any cis or trans co-occurrence observation is available.

VCEP rule
Not applicable under the InSiGHT MSH2 Version 2.0 specification.
Evidence considered
  • The InSiGHT MSH2 Version 2.0 specification lists BP2 applicability as Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the MSH2 VCEP explicitly designates BP3 as Not Applicable, and p.(Thr8Arg) is not an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The MSH2 InSiGHT VCEP specification explicitly designates BP3 as Not Applicable. This variant is a missense substitution, p.(Thr8Arg), rather than an in-frame deletion or insertion in a repetitive region, so the generic BP3 concept does not apply under the governing gene-specific framework. The VCEP-pilot-variants---MMR.xlsx was searched for c.23C>G, p.Thr8Arg, and p.T8R, with no exact entry found.

VCEP rule
MSH2 InSiGHT VCEP v2.0 BP3 applicability: Not Applicable
Evidence considered
  • The MSH2 InSiGHT VCEP specification explicitly marks BP3 as Not Applicable.
  • The case normalization identifies the consequence as missense p.(Thr8Arg), not an in-frame deletion or insertion in a repetitive region.
Still missing
  • No exact c.23C>G, p.Thr8Arg, or p.T8R entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗
BP6 VCEPNot applicable: BP6 is excluded by the VCEP and no exact-variant expert-panel Benign or Likely benign classification exists. Details ▾Hide ▴
Reasoning

The MSH2 InSiGHT VCEP explicitly marks BP6 as not applicable and states that the criterion is not for use. In addition, the exact ClinVar record has no expert-panel submission and therefore no exact-variant expert-panel Benign or Likely benign classification that could satisfy the requested BP6 gate.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The MSH2 InSiGHT VCEP marks BP6 as Not Applicable for this VCEP and states that the criterion is not for use.
  • The exact ClinVar record reports zero expert-panel submissions; the benign and likely benign assertions are ordinary single-submitter laboratory assertions.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: c.23C>G is a missense variant producing p.Thr8Arg, not a synonymous or qualifying intronic variant. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000251.3:c.23C>G produces the missense substitution p.Thr8Arg (p.T8R), so BP7 is outside its criterion scope and no BP7 predictor evaluation is required.

Rule
BP7 applies only to a synonymous (silent) or qualifying intronic variant.
Evidence considered
  • Case normalization identifies NM_000251.3:c.23C>G as NP_000242.1:p.(Thr8Arg) / p.(T8R).
  • The MSH2 VCEP BP7 rule is limited to synonymous or qualifying intronic variants.

Identifiers

Gene
MSH2
Transcript
NM_000251.3
Coding (HGVS c.)
NM_000251.3:c.23C>G
Protein (HGVS p.)
NP_000242.1:p.(Thr8Arg)
GRCh38
chr2:47403214 C>G
GRCh37
chr2:47630353 C>G
Location and type
Exon 1 · missense
ClinVar
408516

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 3 / 1,600,016 alleles AF 1.87e-06 · 0 homozygotes · FAF 4.43e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,600,016 alleles · 0 hom · FAF 4.4e-06
African/African American2 / 74,924 2.7e-05
Remaining individuals1 / 61,948 1.6e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.87498e-06; MAF= 0.00019%, 3/1600016 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66937e-05; MAF= 0.00267%, 2/74924 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.037
Pangolin splice gain
0.056

Other predictors

REVEL
0.516
BayesDel
0.032

How the predictions were used

BP4 SupportingMet, supporting: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP BP4 threshold of <0.11. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000251.3:c.23C>G (p.Thr8Arg/p.T8R), and the governing InSiGHT MSH2 VCEP specification provides a missense BP4 rule based on the HCI prior probability. The exact on-record HCI-PRIORS-MSH2 entry reports a pathogenicity probability of 0.0013, which is <0.11 and therefore directly satisfies BP4_Supporting. The REVEL score is 0.516 and does not independently meet the supplied generic BP4 Supporting threshold of <=0.29; it is not needed because the VCEP HCI rule is met. The available BayesDel score is not interpretable for ACMG strength because no generic calibration is established and the VCEP specifies no BayesDel cutoff.

Rule
Missense variant with HCI prior probability for pathogenicity <0.11 = BP4_Supporting, per the MSH2 InSiGHT VCEP specification.
Evidence considered
  • The MSH2 InSiGHT VCEP specification (version 2.0) defines BP4_Supporting for a missense variant with HCI prior probability <0.11.
  • The on-record HCI-PRIORS-MSH2 table contains the exact c.23C>G / p.T8R entry and reports pathogenicity probability 0.0013.
  • The local REVEL lookup reports 0.516, which is above the supplied generic BP4 Supporting threshold of <=0.29; this alternative path is not met but does not override the VCEP HCI rule.
  • The local BayesDel score is 0.0317561, but no generic ACMG strength calibration is established and the governing MSH2 VCEP provides no BayesDel cutoff, so it is not available for BP4 adjudication.
Sources
cspec ↗vcep_hci_priors_msh2revelbayesdel
PP3 Not met: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP PP3 Supporting threshold of >0.68, and REVEL 0.516 is below 0.644. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000251.3:c.23C>G (p.Thr8Arg/p.T8R), so the MSH2 missense computational path applies. The governing InSiGHT MSH2 VCEP specification assigns PP3_Moderate only when the HCI prior probability is >0.81 and PP3_Supporting when it is >0.68 and <=0.81. The exact HCI lookup entry for c.23C>G reports a pathogenicity probability of 0.0013, which does not meet either VCEP PP3 threshold. The available REVEL score is 0.516, below the supplied generic PP3 Supporting threshold of >=0.644 from ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG strength calibration is established and the MSH2 VCEP does not specify a BayesDel cutoff.

Rule
Missense variant with HCI prior probability for pathogenicity >0.81 = PP3_Moderate; >0.68 and <=0.81 = PP3_Supporting, per the MSH2 InSiGHT VCEP specification.
Evidence considered
  • The MSH2 InSiGHT VCEP specification (version 2.0) governs PP3 and defines PP3_Moderate for missense variants with HCI prior probability >0.81 and PP3_Supporting for >0.68 and <=0.81.
  • The on-record HCI-PRIORS-MSH2 table contains the exact c.23C>G / p.T8R entry and reports pathogenicity probability 0.0013.
  • The local REVEL lookup reports 0.516; the supplied ClinGen SVI calibration threshold for PP3 Supporting is >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The local BayesDel score is 0.0317561, but no generic ACMG strength calibration is established and the governing MSH2 VCEP provides no BayesDel cutoff, so it is not available for PP3 adjudication.
Sources
cspec ↗vcep_hci_priors_msh2revelbayesdel
BP7 N/ANot applicable: c.23C>G is a missense variant producing p.Thr8Arg, not a synonymous or qualifying intronic variant. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_000251.3:c.23C>G produces the missense substitution p.Thr8Arg (p.T8R), so BP7 is outside its criterion scope and no BP7 predictor evaluation is required.

Rule
BP7 applies only to a synonymous (silent) or qualifying intronic variant.
Evidence considered
  • Case normalization identifies NM_000251.3:c.23C>G as NP_000242.1:p.(Thr8Arg) / p.(T8R).
  • The MSH2 VCEP BP7 rule is limited to synonymous or qualifying intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0317561. HCI prior probability for pathogenicity = 0.0013. MAPP score = 3.1. Custom PP2 score = 0.001.

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

  • Informing family members of individuals with Lynch syndrome: a guideline for cli
    This guideline paper does not mention MSH2 c.23C>G or p.(T8R) and provides no variant-specific clinical or phenotype evidence.
    Does not name this variant
    PMID 23535968 ↗
    Quoted passage
    Pedigree data may show, for example, early-onset colorectal cancer in successive generations, suggesting Lynch syndrome, an autosomal dominant condition due to germline mutations in DNA mismatch repair (MMR) genes.

    Introduction, paragraph 1

  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    This ACMG incidental-findings recommendation does not mention MSH2 c.23C>G or p.(T8R) and provides no variant-specific phenotype evidence.
    Does not name this variant
    PMID 23788249 ↗
    Quoted passage
    The Working Group recommended that the laboratory actively search for the specified types of mutations in the specified genes listed in these recommendations.

    Working Group Considerations, The Clinical Utility of Incidental Findings

  • Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.
    Stoffel EM et al. · 2015
    This clinical-practice guideline does not report MSH2 c.23C>G or p.(T8R); it discusses general Lynch syndrome tumor MSI and MMR-protein-loss relationships only.
    Does not name this variant
    PMID 25452455 ↗
    Quoted passage
    These alterations convey a predisposition to develop tumors with phenotypes of DNA microsatellite instability (MSI),3 which often demonstrate loss of expression of the corresponding MMR protein detected by immunohistochemistry (IHC) techniques.4,5

    Introduction, section titled “LS”

  • Standards and guidelines for the interpretation of sequence variants: a joint co
    This general ACMG/AMP guideline does not mention the specific MSH2 variant and provides no variant-specific phenotype, prevalence, or alternate-molecular-basis evidence.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    The impact of a missense change depends on criteria such as the evolutionary conservation of an amino acid or nucleotide, the location and context within the protein sequence, and the biochemical consequence of the amino acid substitution.

    Computational (In Silico) Predictive Programs

  • Genetics of Colorectal Cancer (PDQ®): Health Professional Version.
    No paper-specific finding is recorded.
    PMID 26389505 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite
    This Sherloc framework paper does not mention MSH2 c.23C>G or p.(T8R) and provides no variant-specific clinical or phenotype evidence.
    Does not name this variant
    PMID 28492532 ↗
  • Lynch Syndrome in Urologic Malignancies - What Does the Urologist Need to Know?
    No paper-specific finding is recorded.
    PMID 31302137 ↗
  • Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.
    Jia X et al. · 2021
    The paper does not explicitly mention MSH2 c.23C>G or p.(T8R). It reports a massively parallel functional assay measuring loss-of-function effects for MSH2 missense variants in human MSH2-knockout cells using 6-thioguanine selection. The screen covered 94.4% of possible single-codon substitutions, and the paper states that the N-terminal mismatch-binding domain, which includes residue 8, was largely devoid of missense loss-of-function variants; no variant-specific functional score or observation for p.(T8R) is provided.
    Does not name this variant
    PMID 33357406 ↗
    Quoted passage
    The resulting functional effect map was substantially complete, covering 94.4% of possible MSH2 single-codon substitutions. Missense variant scores were bimodal, with the large majority (89.4%) scoring negatively, suggesting a high degree of tolerance to single amino acid substitution.

    Results, “A functional effect map covering >17,000 MSH2 missense variants,” paragraph 2; Figure 2

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

gnomAD v4.1 3 / 1,600,016 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 3 Uncertain significance · 1 Likely benign · 1 Uncertain Significance · 1 Benign 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= 1.87498e-06; MAF= 0.00019%, 3/1600016 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66937e-05; MAF= 0.00267%, 2/74924 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 408516)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0317561. HCI prior probability for pathogenicity = 0.0013. MAPP score = 3.1. Custom PP2 score = 0.001.

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.