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MSH2c.403C>GUncertain significance
Print report
Variant interpretation report

MSH2 c.403C>G, p.(Leu135Val)

NM_000251.3:c.403C>G NP_000242.1:p.(Leu135Val) Missense · exon 3 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

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: 0 Benign evidence criteria: 0
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: no adjudicated pathogenic or benign-strength criteria were applied under the MSH2 VCEP Version 2.0 combination 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
91 / 1,613,928 alleles

gnomAD v4.1: 91 / 1,613,928 alleles. Recorded AF 5.63842e-05. Recorded homozygote count 2.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 9.94779e-05; MAF= 0.00995%, 25/251312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000489972; MAF= 0.04900%, 15/30614 alleles, homozygotes = 0); grpmax FAF= 0.00030156.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010856584518510477, 2/18422 alleles, homozygotes = 0).

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.275 recorded score

Recorded REVEL score: 0.275. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
15 reported laboratory submissions

9 Uncertain significance · 3 Benign · 2 Likely benign · 1 Likely Benign. ClinVar API review status: criteria provided, conflicting classifications.

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: 0 met · 5 not met · 11 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

NM_000251.3:c.403C>G is a missense SNV (NP_000242.1:p.(Leu135Val)), so it does not enter the VCEP-defined PVS1 null-variant paths.

The MSH2 VCEP explicitly marks PM4 and BP3 as Not Applicable; the missense substitution also produces neither a protein-length change nor an in-frame indel in a repeat region.

For the requested codon, residue, and domain criteria, the governing MSH2 VCEP makes PM1, PP2, and BP1 not applicable; PS1 is not met because no qualifying VCEP Pathogenic same-amino-acid comparator was found; PM5 remains not assessed because no qualifying VCEP-classified alternate missense comparator at residue 135 is available.

Among the requested criteria, PM6 is not applicable under the VCEP specification; PS2, PP1, and BS4 cannot be assessed because case-specific de novo, segregation, and non-segregation data are not documented.

PS4, PP5, and BP6 are not applicable under the MSH2 VCEP rules. PP4 and BP5 are not assessed because the required variant-specific tumor phenotype, MSI/IHC, tumor-genome, BRAF V600E, and MLH1-methylation evidence is not available.

Not met · 5 · evaluated, threshold not reached

PS1 VCEPNot met: no different-nucleotide p.Leu135Val variant is established as Pathogenic by this VCEP. Details ▾Hide ▴
Reasoning

The variant is a predicted missense substitution encoding p.Leu135Val, but the governing VCEP evidence reviewed does not establish a different nucleotide change encoding the same amino-acid change as Pathogenic. The VCEP CSPEC requires prior VCEP Pathogenic classification for that comparator. The on-record HCI table contains the present c.403C>G p.L135V row, but no VCEP Pathogenic same-amino-acid comparator was identified in the governing VCEP files.

VCEP rule
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect). OR Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Evidence considered
  • CSPEC PS1 review: the rule requires a predicted missense substitution encoding the same amino-acid change with a different nucleotide change previously established by this VCEP as Pathogenic, excluding predicted or confirmed splice defects.
  • HCI-PRIORS-MSH2.txt.txt, row 883: c.403C>G, p.L135V, HCI prior 0.311; this is the present variant, not a different-nucleotide VCEP Pathogenic comparator.
  • MMR-Functional-domains.pdf.txt was searched for c.403C>G, p.Leu135Val, and p.L135V; no variant-specific entry was found.
Still missing
  • No governing VCEP-file entry establishing a different-nucleotide p.Leu135Val comparator as Pathogenic was identified; MMR-Functional-domains.pdf was searched and has no variant entry relevant to PS1.
Sources
cspec ↗vcep_hci_priors_msh2 ↗
PM2 VCEPNot met: gnomAD v4.1 total allele frequency is 5.63842e-05, exceeding the VCEP PM2 cutoff of 0.00002. Details ▾Hide ▴
Reasoning

The InSiGHT MSH2 VCEP permits PM2 at Supporting strength only for an allele frequency <0.00002 in the gnomAD v4 dataset. This variant has gnomAD v4.1 total AF 5.63842e-05 (91/1,613,928 alleles), which exceeds 0.00002; therefore PM2 is not met. The exact variant was not found in the searched VCEP-pilot-variants---MMR.xlsx table, so no governing pre-assigned PM2 code was identified there.

VCEP rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles ) in gnomAD v4 dataset
Evidence considered
  • gnomAD v4.1: total AF 5.63842e-05, 91/1,613,928 alleles, with 2 homozygotes; the VCEP PM2 threshold is <0.00002.
  • The VCEP-pilot-variants---MMR.xlsx full-text table was searched for c.403C>G, p.Leu135Val, and p.L135V; no matching row or pre-assigned PM2 code was found.
Still missing
  • No matching c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx; this does not establish absence of population evidence.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr ↗
PP3 VCEPNot met: HCI prior probability is 0.135, below the VCEP PP3 Supporting threshold of >0.68 and the Moderate threshold of >0.81. Details ▾Hide ▴
Reasoning

The VCEP governs PP3 for missense variants using the HCI prior (>0.81 for Moderate or >0.68 and <=0.81 for Supporting), or for predicted splice defects at non-canonical splicing nucleotides using SpliceAI delta >=0.2. This is a missense coding SNV, c.403C>G (p.L135V), and the governing HCI table assigns a pathogenicity prior of 0.135, which meets neither PP3 threshold. The SpliceAI result is not applicable to the missense HCI path and does not establish the separately scoped non-canonical splicing-nucleotide path.

VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Missense variant with HCI prior probability for pathogenicity >0.68 & <=0.81 as per https://hci-priors.hci.utah.edu/PRIORS OR Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH2.txt, row MSH2_00882: c.403C>G / p.L135V, prior probability of pathogenicity = 0.1350.
  • Case normalization identifies NM_000251.3:c.403C>G as the missense variant NP_000242.1:p.(L135V); the VCEP's SpliceAI PP3 alternative is specifically for predicted splice defects at non-canonical splicing nucleotides, not this coding missense path.
Sources
vcep_hci_priors_msh2 ↗
BA1 VCEPNot met: gnomAD v4.1 joint Grpmax filtering allele frequency is 0.00070274, below the VCEP BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency >=0.001 (0.1%) and exclusion as a founder pathogenic variant. The gnomAD v4.1 joint Grpmax filtering allele frequency is 0.00070274 (0.070274%), below 0.001, so BA1 is not met regardless of founder status. The exact variant was not found in the searched VCEP-pilot-variants---MMR.xlsx table.

VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1: joint Grpmax filtering allele frequency 0.00070274; total AF 5.63842e-05 from 91/1,613,928 alleles, with 2 homozygotes.
  • The VCEP-pilot-variants---MMR.xlsx full-text table was searched for c.403C>G, p.Leu135Val, and p.L135V; no matching row was found.
Still missing
  • No matching c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx; this does not establish absence of population evidence.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr ↗
BP4 VCEPNot met: HCI prior probability is 0.1350, above the VCEP BP4 missense threshold of <0.11; its SpliceAI alternative does not cover missense variants. Details ▾Hide ▴
Reasoning

The VCEP governs BP4 for missense variants using an HCI prior <0.11, or for intronic and synonymous variants using SpliceAI delta <=0.1. This variant is missense c.403C>G (p.L135V), and its governing HCI-table prior is 0.1350, not <0.11. The SpliceAI alternative is limited by the rule to intronic and synonymous variants, so the observed maximum delta score of 0.01 cannot be used for BP4 here.

VCEP rule
Missense variant with HCI-prior probability of pathogenicity \<0.11 as per https://hci-priors.hci.utah.edu/PRIORS OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score \<= 0.1 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH2.txt, row MSH2_00882: c.403C>G / p.L135V, prior probability of pathogenicity = 0.1350; this does not satisfy the VCEP BP4 cutoff of <0.11.
  • SpliceAI result for NM_000251.3:c.403C>G: maximum delta score = 0.01, but the VCEP BP4 SpliceAI alternative is restricted to intronic and synonymous variants and therefore is not applicable to this missense variant.
Sources
vcep_hci_priors_msh2 ↗

Not assessed · 11 · no assessment recorded

PS2 VCEPNot assessed: no proband-level de novo observation or parental testing is documented, so the VCEP's de novo-point thresholds cannot be applied. Details ▾Hide ▴
Reasoning

No case-specific proband-level de novo observation, parental testing, maternity/paternity confirmation, or de novo point assignment is documented. The VCEP provides point-based PS2 thresholds, but the available evidence does not establish any de novo points.

VCEP rule
de novo point thresholds
Evidence considered
  • The case-specific evidence contains no documented proband de novo result, parental testing result, or de novo point assignment for NM_000251.3:c.403C>G (NP_000242.1:p.(Leu135Val)).
Still missing
  • Documented de novo status for the proband variant.
  • Parental genotypes and confirmation of maternity/paternity.
  • VCEP de novo point assignment, if applicable.
PS3 VCEPNot assessed: no variant-specific calibrated functional result or functional odds are reported for MSH2 c.403C>G (p.Leu135Val). Details ▾Hide ▴
Reasoning

The variant is a missense change, so PS3 is applicable under the MSH2 VCEP. The VCEP's calibrated functional-assay documentation identifies validated MSH2 assays and their calibration framework, including the chemical-selection/deep-sequencing assay (PMIDs 33357406 and 36550560) with LOF score >0.4 as abnormal and proposed PS3/BS3 use, but the table contains no variant-specific entry for c.403C>G, p.Leu135Val, or p.L135V. The functional-assay flowchart provides only a general pathway for missense variants without a variant-specific result. The case evidence bundle and its paper extracts likewise contain no variant-specific functional assay result; the extracted PON-MMR paper finding is computational and not functional. Therefore, no calibrated functional odds, concordant assay result, or variant-specific MMR function defect is available to meet any PS3 strength.

VCEP rule
PS3
Evidence considered
  • Functional-assay-SVI-documentation-MMR.xlsx, MMR assays sheet: the calibrated chemical-selection/deep-sequencing MSH2 assay is listed with PMIDs 33357406 and 36550560, LOF score >0.4 as the abnormal-readout threshold, 22 P/LP and 26 B/LB validation controls, and proposed PS3/BS3 use; no row for c.403C>G, p.Leu135Val, or p.L135V is present.
  • Functional-assay-flowchart.pdf: the searchable text contains no variant-specific entry; the associated VCEP summary gives only the general missense workflow and requires a calibrated result or concordant independent assays.
  • The case paper extracts contain no variant-specific functional assay finding for MSH2 c.403C>G; PMID:22290698 lists L135V only as an in-silico PON-MMR prediction, not a functional assay.
Still missing
  • Functional-assay-SVI-documentation-MMR.xlsx was searched for c.403C>G, p.Leu135Val, and p.L135V; no exact variant entry was found.
  • Functional-assay-flowchart.pdf was searched for c.403C>G, p.Leu135Val, and p.L135V; no exact variant entry was found.
  • A variant-specific calibrated assay readout, functional odds, or concordant MMR function-defect result is unavailable.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗
PM3 VCEPNot assessed: no documented CMMRD-phenotype proband carried this variant with a second pathogenic/likely pathogenic MSH2 variant, so no PM3 points could be assigned. Details ▾Hide ▴
Reasoning

The VCEP PM3 criterion is applicable and requires co-occurrence of this variant with a known pathogenic/likely pathogenic variant in the same gene in a patient with clinical features consistent with CMMRD. The available case evidence does not document a CMMRD-phenotype proband carrying NM_000251.3:c.403C>G with a second pathogenic/likely pathogenic MSH2 variant, nor does it document phase established by parental or offspring testing. Therefore, no PM3 points can be assigned and the criterion is not assessed.

VCEP 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;** ... Pathogenic/Likely Pathogenic - phase unknown: **0.5 points** ... Sum all cases with the above evidence to determine the PM3 strength.
Evidence considered
  • No case-level report in the reviewed evidence documents a CMMRD phenotype, an affected proband with a second known pathogenic/likely pathogenic MSH2 variant, or phase of NM_000251.3:c.403C>G relative to another MSH2 variant.
  • The VCEP assigns 1.0 point for a pathogenic/likely pathogenic variant in trans and 0.5 points when phase is unknown; neither qualifying observation is documented here.
Still missing
  • A CMMRD-phenotype proband carrying NM_000251.3:c.403C>G and a second known pathogenic/likely pathogenic MSH2 variant is not documented.
  • Phase information from testing of parents or offspring is not available.
  • The clinical features needed to establish CMMRD under the VCEP-referenced criteria are not available.
Sources
cspec ↗
PM5 VCEPNot assessed: no qualifying different missense variant at residue 135 has a governing VCEP Pathogenic or Likely Pathogenic classification. Details ▾Hide ▴
Reasoning

PM5 requires a different missense change at residue 135 classified by the VCEP as Pathogenic or Likely Pathogenic at the protein level and not because of aberrant splicing; the VCEP additionally requires PP3 supporting for the observed missense change. The available PM5 comparator collection identified no same-residue candidates, and the governing VCEP files do not provide a qualifying prior VCEP classification for another residue-135 missense variant. Therefore the criterion cannot be assessed from the permitted evidence.

VCEP rule
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5\_Supporting if other variant is Likely Pathogenic due to a missense alteration. ... Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5\_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.
Evidence considered
  • CSPEC PM5 rule: a different missense change at the same amino-acid residue must be classified by this VCEP as Pathogenic or Likely Pathogenic at the protein level and not due to aberrant splicing; PM5 requires PP3 supporting for the observed missense change.
  • pm5_candidates.json: classic_same_residue_missense mode; total candidates seen 10, same_residue_candidates 0, expert_panel_plp_candidates 0, and non_expert_majority_plp_candidates 0.
  • HCI-PRIORS-MSH2.txt.txt contains other substitutions at residue 135 (including c.403C>A p.L135I, c.403C>T p.L135F, c.404T>A p.L135H, c.404T>C p.L135P, and c.404T>G p.L135R), but those rows are prior-prediction records, not VCEP Pathogenic or Likely Pathogenic classifications.
Still missing
  • A qualifying VCEP-classified Pathogenic or Likely Pathogenic different missense comparator at MSH2 residue 135 is not available in the reviewed evidence.
  • The PM5 candidate collection reported zero same-residue candidates after retrieval failure; direct VCEP comparator evidence would be needed.
Sources
cspec ↗pm5_candidatesvcep_hci_priors_msh2 ↗
PP1 VCEPNot assessed: no informative meioses or combined Bayes likelihood ratio is documented, so the VCEP PP1 thresholds cannot be evaluated. Details ▾Hide ▴
Reasoning

No affected-relative segregation data, unaffected-relative genotype data, informative meioses, pedigree-level likelihood ratio, or combined Bayes likelihood ratio is documented for this variant. The VCEP PP1 thresholds therefore cannot be evaluated.

VCEP rule
combined Bayes likelihood ratio thresholds
Evidence considered
  • The case-specific evidence does not report affected or unaffected relatives, familial variant testing, informative meioses, or a combined Bayes likelihood ratio for NM_000251.3:c.403C>G.
Still missing
  • Pedigree with affected and unaffected relatives and variant genotypes.
  • Informative meioses and phenotype classification for each tested relative.
  • Combined Bayes likelihood ratio and number of families.
Sources
PMID:22290698 ↗
PP4 VCEPNot assessed: no eligible MSI-H tumor or MSH2-consistent MMR-protein loss is documented to meet the VCEP PP4 rule. Details ▾Hide ▴
Reasoning

The VCEP PP4 rule requires one or more independent CRC/endometrial MSI-H tumors or tumor-genome/MSH2-consistent MMR-protein loss, with higher strengths requiring specified numbers of independent tumors and families. The available case evidence does not document an eligible tumor, MSI result, tumor-genome result, MMR immunohistochemistry result, or consistency with the MSH2 variant location. The on-record Table-for-CMMRD-diagnosis.pdf and VCEP-pilot-variants---MMR.xlsx files were searched for c.403C>G, p.Leu135Val, and p.L135V; neither contains an exact entry for this variant.

VCEP rule
1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers<sup>e</sup> or tumor genome **and/or** loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.
Evidence considered
  • The VCEP PP4 Supporting rule requires '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.'
  • The available case bundle contains no variant-specific MSI, IHC, tumor-genome, or eligible clinical tumor observation for NM_000251.3:c.403C>G (p.Leu135Val).
  • Table-for-CMMRD-diagnosis.pdf.txt was searched for c.403C>G, p.Leu135Val, and p.L135V with no matching row.
  • VCEP-pilot-variants---MMR.xlsx.txt was searched for c.403C>G, p.Leu135Val, and p.L135V with no matching row.
Still missing
  • Patient or family tumor phenotype and MSI/IHC or tumor-genome results are unavailable.
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in Table-for-CMMRD-diagnosis.pdf.txt.
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis ↗vcep_vcep_pilot_variants_mmr ↗
BS1 VCEPNot assessed: gnomAD v4.1 Grpmax filtering allele frequency is 0.00070274 within range, but founder-pathogenic-variant exclusion is not documented. Details ▾Hide ▴
Reasoning

The InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001 and confirmation that the variant is excluded as a founder pathogenic variant. The gnomAD v4.1 joint Grpmax filtering allele frequency is 0.00070274, within the frequency interval, but the available case evidence does not establish the required founder-pathogenic-variant exclusion. Therefore BS1 cannot be fully evaluated and is not_assessed.

VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1: joint Grpmax filtering allele frequency 0.00070274, which is >=0.0001 and <0.001.
  • No founder-pathogenic-variant exclusion evidence was available in the reviewed case materials.
Still missing
  • The case evidence does not document that this variant is excluded as a founder pathogenic variant, as required by the VCEP BS1 rule.
Sources
cspec ↗gnomad_v4 ↗
BS2 VCEPNot assessed: no eligible in-trans co-occurrence, cancer-age, CMMRD, or parent/offspring phase evidence is available. Details ▾Hide ▴
Reasoning

The InSiGHT MSH2 VCEP BS2 rule requires documented co-occurrence in trans with a known pathogenic variant in the same gene, an eligible cancer presentation after the specified age threshold, no evidence of CMMRD, and phase confirmation through parental or offspring testing. No such patient-level co-occurrence, clinical, CMMRD, or phase evidence is available for this variant, so BS2 is not_assessed.

VCEP rule
Co-occurrence _​in trans​_ with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS​<sup>d</sup>), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.
Evidence considered
  • The available case evidence contains no qualifying BS2 co-occurrence, clinical age, CMMRD, or phase-confirmation record.
Still missing
  • No patient-level in-trans co-occurrence with a known pathogenic MSH2 variant was documented.
  • No qualifying cancer age, absence of CMMRD manifestations, or parent/offspring phase confirmation was documented.
Sources
cspec ↗
BS3 VCEPNot assessed: no variant-specific proficient-function result or calibrated benign functional odds are reported for MSH2 c.403C>G (p.Leu135Val). Details ▾Hide ▴
Reasoning

The variant is a missense change, so BS3 is applicable under the MSH2 VCEP. The VCEP's calibrated functional-assay documentation identifies validated MSH2 assays and benign-function calibration, including the chemical-selection/deep-sequencing assay (PMIDs 33357406 and 36550560), but the table contains no variant-specific entry for c.403C>G, p.Leu135Val, or p.L135V. The functional-assay flowchart provides only a general pathway and no variant-specific proficient-function result. The case evidence bundle and paper extracts contain no variant-specific functional assay result or calibrated functional odds for this variant. Therefore, the evidence cannot establish BS3 at strong or supporting strength.

VCEP rule
BS3
Evidence considered
  • Functional-assay-SVI-documentation-MMR.xlsx, MMR assays sheet: the calibrated chemical-selection/deep-sequencing MSH2 assay is listed with PMIDs 33357406 and 36550560 and proposed BS3 use, but no row for c.403C>G, p.Leu135Val, or p.L135V is present.
  • Functional-assay-flowchart.pdf: the searchable text contains no variant-specific entry; the associated VCEP summary gives only the general missense workflow and does not provide a proficient-function result for this variant.
  • The case paper extracts contain no variant-specific functional assay finding for MSH2 c.403C>G; PMID:22290698 is an in-silico PON-MMR prediction and does not establish proficient function.
Still missing
  • Functional-assay-SVI-documentation-MMR.xlsx was searched for c.403C>G, p.Leu135Val, and p.L135V; no exact variant entry was found.
  • Functional-assay-flowchart.pdf was searched for c.403C>G, p.Leu135Val, and p.L135V; no exact variant entry was found.
  • A variant-specific calibrated assay readout, functional odds, or proficient-function result is unavailable.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗
BS4 VCEPNot assessed: no non-segregating relatives or combined Bayes likelihood ratio is documented, so the VCEP BS4 thresholds cannot be evaluated. Details ▾Hide ▴
Reasoning

No documented non-segregation with disease, unaffected carrier observations, informative pedigree, or combined Bayes likelihood ratio is available for this variant. The VCEP BS4 thresholds therefore cannot be evaluated.

VCEP rule
combined Bayes likelihood ratio thresholds
Evidence considered
  • The case-specific evidence does not report unaffected variant carriers, non-segregation with disease, or a combined Bayes likelihood ratio for NM_000251.3:c.403C>G.
Still missing
  • Documented unaffected relatives carrying the variant or other non-segregation observations.
  • Pedigree phenotype and genotype data sufficient for likelihood calculation.
  • Combined Bayes likelihood ratio.
BP5 VCEPNot assessed: no qualifying MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor result is documented for BP5. Details ▾Hide ▴
Reasoning

The VCEP BP5 Supporting rule requires two or three qualifying tumors with MSS, no MMR-protein loss, or MMR-protein loss inconsistent with the gene demonstrating genetic variation, or one qualifying BRAF V600E or MLH1-methylated MSI-H tumor. The available evidence documents none of these tumor findings, so BP5 cannot be assessed.

VCEP rule
2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors<sup>d</sup> with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation. OR  1 BRAF V600E (Colon only)/_MLH1_ methylation (in LS spectrum tumor only) with MSI-H/_MLH1_ loss.
Evidence considered
  • The VCEP BP5 Supporting rule requires '2 or 3 tumors' meeting specified MSS/MMR-protein findings or '1 BRAF V600E (Colon only)/MLH1 methylation' finding with MSI-H/MLH1 loss; no such variant-specific tumor evidence is available.
Still missing
  • Tumor count and tumor-level MSS/IHC, BRAF V600E, and MLH1-methylation results are unavailable.
Sources
cspec ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.403C>G is a missense SNV (p.Leu135Val), not one of the VCEP-defined premature-termination, splice-disrupting, or genomic-alteration PVS1 paths. Details ▾Hide ▴
Reasoning

NM_000251.3:c.403C>G is an SNV with the missense consequence NP_000242.1:p.(Leu135Val), not a nonsense, frameshift, canonical splice-site, large genomic alteration, or patient-RNA-confirmed truncating/splicing variant. The MSH2 VCEP PVS1 rule is limited to the specified premature-termination, genomic-alteration, splice-disrupting, and qualifying patient-RNA paths; this missense substitution does not enter any of those paths, so PVS1 is not applicable and no strength tier is assigned. The exact variant was not found in PVS1_DecisionTree_MMR.pdf or VCEP-pilot-variants---MMR.xlsx under c.403C>G, p.Leu135Val, or p.L135V.

VCEP rule
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)<sup>a</sup> ≤ codon 891 in _MSH2._ Refer to Appendix for details.
Evidence considered
  • Case normalization identifies NM_000251.3:c.403C>G as NP_000242.1:p.(Leu135Val)/p.(L135V); VEP reports most_severe_consequence missense_variant and variant_class SNV.
  • The VCEP cspec PVS1 entry specifies nonsense/frameshift variants introducing a premature termination codon at or before codon 891 in MSH2, large single- or multi-exon genomic alterations, qualifying splice-site variants, or qualifying patient-RNA-confirmed splicing aberrations; this missense SNV matches none of those categories.
  • PVS1_DecisionTree_MMR.pdf.txt was searched for c.403C>G, p.Leu135Val, and p.L135V with no exact variant entry.
  • VCEP-pilot-variants---MMR.xlsx.txt was searched for c.403C>G, p.Leu135Val, and p.L135V with no exact variant entry.
Still missing
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in PVS1_DecisionTree_MMR.pdf.txt.
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_pvs1_decisiontree_mmr ↗vcep_vcep_pilot_variants_mmr ↗
PS4 VCEPNot applicable: the MSH2 VCEP excludes PS4 proband-counting classification because tumor IHC evidence is evaluated through PP4. Details ▾Hide ▴
Reasoning

The MSH2 VCEP marks PS4 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 through PP4. No PS4 threshold or case-control calculation is therefore applied.

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 VCEP CSPEC entry for PS4 states: '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.'
Sources
cspec ↗
PM1 VCEPNot applicable: the MSH2 VCEP recognizes no usable mutational hotspot or domain-based PM1 path. Details ▾Hide ▴
Reasoning

The MSH2 VCEP marks PM1 Not applicable and states that there are no recognized mutational hotspots usable for classification and that pathogenic variants are generalized across MMR functional domains. vcep_materials.json has no authoritative domain_tables entry for MSH2; the governing MMR-Functional-domains file was searched as required, but it provides no variant-specific exception to the VCEP's PM1 applicability decision.

VCEP rule
There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains (unpublished data).
Evidence considered
  • CSPEC PM1 instructions: no recognized mutational hotspots can be used for classification, and pathogenic variants are distributed across MMR functional domains.
  • MMR-Functional-domains.pdf.txt was searched for c.403C>G, p.Leu135Val, and p.L135V; no variant-specific entry was found.
  • vcep_materials.json domain_tables is empty, so no authoritative MSH2 domain-table entry overrides the VCEP PM1 Not applicable designation.
Sources
cspec ↗vcep_mmr_functional_domains ↗
PM4 VCEPNot applicable: the MSH2 VCEP explicitly excludes PM4, and c.403C>G changes one amino acid without changing protein length. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT MSH2 VCEP criteria entry explicitly marks PM4 as Not Applicable. Independently, NM_000251.3:c.403C>G is a missense SNV causing p.(Leu135Val), with no in-frame insertion/deletion, stop-loss event, or protein-length change to evaluate. The exact variant was not found in PVS1_DecisionTree_MMR.pdf or VCEP-pilot-variants---MMR.xlsx under c.403C>G, p.Leu135Val, or p.L135V.

VCEP rule
Not Applicable
Evidence considered
  • The VCEP cspec criteria entry for PM4 has applicability set to Not Applicable.
  • Case normalization and VEP identify c.403C>G/p.(Leu135Val) as a missense SNV, so there is no in-frame indel or protein-length change.
  • PVS1_DecisionTree_MMR.pdf.txt and VCEP-pilot-variants---MMR.xlsx.txt were searched for all three variant notations; neither contained an exact entry.
Still missing
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in PVS1_DecisionTree_MMR.pdf.txt.
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_pvs1_decisiontree_mmr ↗vcep_vcep_pilot_variants_mmr ↗
PM6 VCEPNot applicable: the MSH2 VCEP explicitly marks PM6 Not Applicable, so no PM6 evidence is evaluated. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT MSH2 VCEP specification explicitly marks PM6 as Not Applicable; therefore this criterion is not evaluated for this variant.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT MSH2 specification v2.0, CSPEC criterion entry for PM6: applicability is listed as Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the MSH2 VCEP explicitly excludes PP2 for missense variants in this gene. Details ▾Hide ▴
Reasoning

The MSH2 VCEP explicitly marks PP2 Not applicable because the missense-variant criterion does not apply to this gene under its specification.

VCEP rule
Missense variant in a gene with low rate of benign missense changes does not apply.
Evidence considered
  • CSPEC PP2 instructions state that a missense variant in a gene with a low rate of benign missense changes does not apply.
Sources
cspec ↗
PP5 VCEPNot applicable: the MSH2 VCEP prohibits PP5 use regardless of reported pathogenic classifications. Details ▾Hide ▴
Reasoning

The MSH2 VCEP explicitly marks PP5 not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No literature classification is used as PP5.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP PP5 entry states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗
BP1 VCEPNot applicable: the MSH2 VCEP explicitly excludes BP1 for missense variants in this gene. Details ▾Hide ▴
Reasoning

The MSH2 VCEP explicitly marks BP1 Not applicable because this gene is not treated as a gene in which only loss of function causes disease for purposes of the missense BP1 criterion.

VCEP rule
Missense variant in a gene where only loss of function causes disease is not applicable.
Evidence considered
  • CSPEC BP1 instructions state that a missense variant in a gene where only loss of function causes disease is not applicable.
Sources
cspec ↗
BP2 VCEPNot applicable: the VCEP states that BP2 is not used and that BS2 is used instead. Details ▾Hide ▴
Reasoning

BP2 is not applicable under the InSiGHT MSH2 VCEP specification because the specification directs that BS2 is used instead. No BP2 evidence assessment is therefore performed.

VCEP rule
BS2 is used instead.
Evidence considered
  • The VCEP BP2 entry states: “BS2 is used instead.”
Sources
cspec ↗
BP3 VCEPNot applicable: the MSH2 VCEP explicitly excludes BP3, and c.403C>G is a missense SNV rather than an in-frame indel in a repeat region. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT MSH2 VCEP criteria entry explicitly marks BP3 as Not Applicable. Independently, NM_000251.3:c.403C>G is a missense SNV causing p.(Leu135Val), not an in-frame insertion/deletion in a repetitive region, so BP3 has no applicable variant type or repeat-context path. The exact variant was not found in PVS1_DecisionTree_MMR.pdf or VCEP-pilot-variants---MMR.xlsx under c.403C>G, p.Leu135Val, or p.L135V.

VCEP rule
Not Applicable
Evidence considered
  • The VCEP cspec criteria entry for BP3 has applicability set to Not Applicable.
  • Case normalization and VEP identify c.403C>G/p.(Leu135Val) as a missense SNV, not an in-frame insertion/deletion; no repeat-region context can make BP3 applicable.
  • PVS1_DecisionTree_MMR.pdf.txt and VCEP-pilot-variants---MMR.xlsx.txt were searched for all three variant notations; neither contained an exact entry.
Still missing
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in PVS1_DecisionTree_MMR.pdf.txt.
  • No exact c.403C>G, p.Leu135Val, or p.L135V entry was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_pvs1_decisiontree_mmr ↗vcep_vcep_pilot_variants_mmr ↗
BP6 VCEPNot applicable: the MSH2 VCEP prohibits BP6 use regardless of reported benign classifications. Details ▾Hide ▴
Reasoning

The MSH2 VCEP explicitly marks BP6 not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP BP6 entry states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗
BP7 N/ANot applicable: c.403C>G is a missense variant producing p.L135V, whereas VCEP BP7 covers only synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous or intronic variants at or beyond the specified splice-proximal boundaries. NM_000251.3:c.403C>G produces the missense substitution p.L135V, so it is outside BP7 scope and no BP7 evidence is assessed.

VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Case normalization identifies NM_000251.3:c.403C>G as NP_000242.1:p.(L135V), a missense substitution rather than a synonymous or intronic variant.

Identifiers

Gene
MSH2
Transcript
NM_000251.3
Coding (HGVS c.)
NM_000251.3:c.403C>G
Protein (HGVS p.)
NP_000242.1:p.(Leu135Val)
GRCh38
chr2:47410130 C>G
GRCh37
chr2:47637269 C>G
Location and type
Exon 3 · missense
ClinVar
187103

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 91 / 1,613,928 alleles AF 5.64e-05 · 2 homozygotes · FAF 0.000703
gnomAD v2.1 25 / 251,312 alleles AF 9.95e-05 · 0 homozygotes · FAF 0.000302
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.6e-05 · 91 / 1,613,928 alleles · 2 hom · FAF 0.0007
South Asian78 / 91,082 0.000862 hom
Admixed American1 / 59,992 1.7e-05
Remaining individuals1 / 62,480 1.6e-05
European (non-Finnish)11 / 1,179,926 9.3e-06
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 9.9e-05 · 25 / 251,312 alleles · 0 hom · FAF 0.0003
South Asian15 / 30,614 0.00049
European (non-Finnish)9 / 113,622 7.9e-05
Admixed American1 / 34,572 2.9e-05
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.63842e-05; MAF= 0.00564%, 91/1613928 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.000856371; MAF= 0.08564%, 78/91082 alleles, homozygotes = 2); grpmax FAF= 0.00070274.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 9.94779e-05; MAF= 0.00995%, 25/251312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000489972; MAF= 0.04900%, 15/30614 alleles, homozygotes = 0); grpmax FAF= 0.00030156.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010856584518510477, 2/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +177 bp
0.006
SpliceAI acceptor gainat +61 bp
0.002
SpliceAI donor lossat -129 bp
0.002
SpliceAI donor gainat +88 bp
0.002
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.002

Other predictors

REVEL
0.275
BayesDel
0.267

How the predictions were used

PP3 VCEPNot met: HCI prior probability is 0.135, below the VCEP PP3 Supporting threshold of >0.68 and the Moderate threshold of >0.81. Details ▾Hide ▴
Reasoning

The VCEP governs PP3 for missense variants using the HCI prior (>0.81 for Moderate or >0.68 and <=0.81 for Supporting), or for predicted splice defects at non-canonical splicing nucleotides using SpliceAI delta >=0.2. This is a missense coding SNV, c.403C>G (p.L135V), and the governing HCI table assigns a pathogenicity prior of 0.135, which meets neither PP3 threshold. The SpliceAI result is not applicable to the missense HCI path and does not establish the separately scoped non-canonical splicing-nucleotide path.

VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS) ... Missense variant with HCI prior probability for pathogenicity >0.68 & <=0.81 as per https://hci-priors.hci.utah.edu/PRIORS OR Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH2.txt, row MSH2_00882: c.403C>G / p.L135V, prior probability of pathogenicity = 0.1350.
  • Case normalization identifies NM_000251.3:c.403C>G as the missense variant NP_000242.1:p.(L135V); the VCEP's SpliceAI PP3 alternative is specifically for predicted splice defects at non-canonical splicing nucleotides, not this coding missense path.
Sources
vcep_hci_priors_msh2 ↗
BP4 VCEPNot met: HCI prior probability is 0.1350, above the VCEP BP4 missense threshold of <0.11; its SpliceAI alternative does not cover missense variants. Details ▾Hide ▴
Reasoning

The VCEP governs BP4 for missense variants using an HCI prior <0.11, or for intronic and synonymous variants using SpliceAI delta <=0.1. This variant is missense c.403C>G (p.L135V), and its governing HCI-table prior is 0.1350, not <0.11. The SpliceAI alternative is limited by the rule to intronic and synonymous variants, so the observed maximum delta score of 0.01 cannot be used for BP4 here.

VCEP rule
Missense variant with HCI-prior probability of pathogenicity \<0.11 as per https://hci-priors.hci.utah.edu/PRIORS OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score \<= 0.1 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH2.txt, row MSH2_00882: c.403C>G / p.L135V, prior probability of pathogenicity = 0.1350; this does not satisfy the VCEP BP4 cutoff of <0.11.
  • SpliceAI result for NM_000251.3:c.403C>G: maximum delta score = 0.01, but the VCEP BP4 SpliceAI alternative is restricted to intronic and synonymous variants and therefore is not applicable to this missense variant.
Sources
vcep_hci_priors_msh2 ↗
BP7 N/ANot applicable: c.403C>G is a missense variant producing p.L135V, whereas VCEP BP7 covers only synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous or intronic variants at or beyond the specified splice-proximal boundaries. NM_000251.3:c.403C>G produces the missense substitution p.L135V, so it is outside BP7 scope and no BP7 evidence is assessed.

VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Case normalization identifies NM_000251.3:c.403C>G as NP_000242.1:p.(L135V), a missense substitution rather than a synonymous or intronic variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.275. BayesDel score = 0.267297. HCI prior probability for pathogenicity = 0.135. MAPP score = 14.17. Custom PP2 score = 0.311.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • Classification of mismatch repair gene missense variants with PON-MMR.
    Ali H et al. · 2012
    The exact MSH2 protein variant p.Leu135Val is listed as a neutral prediction in PON-MMR, but the paper reports no variant-specific clinical observation, segregation result, or family-based likelihood calculation for this variant.
    Names this variant
    PMID 22290698 ↗
    Quoted passage
    L135V

    Table 3, ‘Predicted Pathogenic and Neutral MMR Missense Variants,’ under Neutral → MSH2

  • Guidelines on genetic evaluation and management of Lynch syndrome: a consensus s
    No paper-specific finding is recorded.
    PMID 25070057 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint co
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    No paper-specific finding is recorded.
    PMID 26389210 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm.
    Morris B et al. · 2016
    No paper-specific finding is recorded.
    PMID 27363726 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite
    No paper-specific finding is recorded.
    PMID 28492532 ↗
  • Rare loss of function variants in candidate genes and risk of colorectal cancer.
    Rosenthal EA et al. · 2018
    No paper-specific finding is recorded.
    PMID 30267214 ↗

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

gnomAD v4.1 91 / 1,613,928 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.006 Open source ↗
ClinVar 9 Uncertain significance · 3 Benign · 2 Likely benign · 1 Likely 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= 5.63842e-05; MAF= 0.00564%, 91/1613928 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.000856371; MAF= 0.08564%, 78/91082 alleles, homozygotes = 2); grpmax FAF= 0.00070274.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 9.94779e-05; MAF= 0.00995%, 25/251312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000489972; MAF= 0.04900%, 15/30614 alleles, homozygotes = 0); grpmax FAF= 0.00030156.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010856584518510477, 2/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 187103)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.275. BayesDel score = 0.267297. HCI prior probability for pathogenicity = 0.135. MAPP score = 14.17. Custom PP2 score = 0.311.

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.