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MLH1c.1897-7C>TUncertain significance
Print report
Variant interpretation report

MLH1 c.1897-7C>T, p.?

NM_000249.4:c.1897-7C>T NP_000240.1:p.? Unknown · intron 16 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 MLH1

MLH1 encodes a DNA mismatch repair protein that, together with partners such as PMS2, corrects errors that arise during DNA replication. Loss of this repair function leads to the accumulation of mutations, particularly in repetitive microsatellite sequences, and tumors with defective MLH1 typically show high microsatellite instability. Germline mutations in MLH1 cause Lynch syndrome (hereditary non-polyposis colorectal cancer), which strongly predisposes to colorectal, endometrial, ovarian, and other cancers, while biallelic mutations cause constitutional mismatch repair deficiency (CMMRD). Because it normally protects against cancer by maintaining genomic stability, MLH1 acts as a tumor suppressor, and mismatch-repair-deficient tumors often respond well to immunotherapy.

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 MLH1 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: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met at Supporting: SpliceAI maximum delta score 0.099 meets the VCEP BP4 no-impact cutoff of <=0.1 for intronic variants.

Recorded classification: Uncertain significance

VUS: BP4 (supporting) is the only applied criterion, so the MLH1 VCEP's requirement for at least two benign supporting criteria is not met.

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
38 / 1,609,460 alleles

gnomAD v4.1: 38 / 1,609,460 alleles. Recorded AF 2.36104e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.099 maximum delta

Recorded SpliceAI maximum delta score: 0.099. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
9 reported laboratory submissions

7 Likely benign · 2 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 4 not met · 10 not assessed · 13 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

PS2, PP1, and BS4 are not assessed because the available case materials contain no variant-level de novo, segregation, non-segregation, pedigree, meiosis, or Bayes Likelihood Ratio evidence; PM6 is Not Applicable under the MLH1 VCEP specification.

Within this group, PS4, PP5, and BP6 are not applicable under the MLH1 VCEP. PP4 and BP5 remain not assessed because the required patient-specific tumor phenotype evidence is unavailable.

The declared Table-for-CMMRD-diagnosis.pdf and VCEP-pilot-variants---MMR.xlsx files were both searched for c.1897-7C>T and p.?; neither contains an exact entry for this variant.

Met · 1

BP4 SupportingVCEPMet at Supporting: SpliceAI maximum delta score 0.099 meets the VCEP BP4 no-impact cutoff of <=0.1 for intronic variants. Details ▾Hide ▴
Reasoning

The variant is intronic, making the VCEP intronic/synonymous SpliceAI path applicable. SpliceAI predicts no splicing impact with a maximum delta score of 0.099, which meets the VCEP cutoff of <=0.1; BP4 is therefore met at Supporting strength. The HCI-PRIORS-MLH1.txt.txt file was searched for c.1897-7C>T and p.? and contains no exact entry, but its governing index limits that lookup to missense substitutions.

VCEP rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023
Evidence considered
  • NM_000249.4:c.1897-7C>T is an intronic variant, so the VCEP intronic SpliceAI path applies.
  • SpliceAI scores for the exact variant are DS_AG 0.099, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.001; maximum delta score = 0.099, at or below the VCEP BP4 cutoff of 0.1.
  • HCI-PRIORS-MLH1.txt.txt was searched for c.1897-7C>T and p.?; no exact row was found, and the index defines that table for missense substitutions.
Still missing
  • No exact c.1897-7C>T or p.? entry was found in HCI-PRIORS-MLH1.txt.txt; that governing lookup is limited to missense substitutions and is not applicable to this intronic variant.
Sources
cspec ↗spliceai ↗

Not met · 4 · evaluated, threshold not reached

PM2 VCEPNot met: gnomAD v4.1 total AF is 2.36104e-05, exceeding the VCEP PM2 cutoff of <0.00002. Details ▾Hide ▴
Reasoning

The MLH1 VCEP specifies PM2 Supporting for an absent or extremely rare allele frequency below 0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset. gnomAD v4.1 reports total AF 2.3610403489369106e-05 and grpmax FAF 2.081e-05, both above 0.00002, so the PM2 threshold is not met. The governing VCEP pilot-variant file was searched for c.1897-7C>T and p.? and contained no matching row.

VCEP rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles ) in gnomAD v4 dataset
Evidence considered
  • ClinGen InSiGHT MLH1 specification v2.0, PM2 rule: absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
  • gnomAD v4.1: variant 3-37048510-C-T; total AF=2.3610403489369106e-05 (38/1609460 alleles), grpmax FAF=2.081e-05, homozygotes=0.
  • VCEP-pilot-variants---MMR.xlsx, Sheet1: searches for c.1897-7C>T and p.? returned no matching row.
Still missing
  • VCEP-pilot-variants---MMR.xlsx was searched for c.1897-7C>T and p.?; no matching entry was found.
Sources
cspec ↗gnomad_v4 ↗vcep_vcep_pilot_variants_mmr ↗
PP3 VCEPNot met: SpliceAI maximum delta score 0.099 is below the VCEP PP3 threshold of 0.2 for a predicted non-canonical splice defect. Details ▾Hide ▴
Reasoning

The variant is a non-canonical intronic substitution, so the applicable VCEP PP3 path is the SpliceAI predicted-splice-defect path. SpliceAI reports a maximum delta score of 0.099 (DS_AG 0.099; all other DS values <=0.005), which is below the VCEP threshold of >=0.2. The HCI-PRIORS-MLH1.txt.txt file was searched for c.1897-7C>T and p.? and contains no exact entry; its missense-only lookup path therefore does not apply to this intronic variant.

VCEP rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
  • NM_000249.4:c.1897-7C>T is intronic and non-canonical; the protein annotation is NP_000240.1:p.?.
  • SpliceAI scores for the exact variant are DS_AG 0.099, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.001; maximum delta score = 0.099, below the VCEP PP3 threshold of >=0.2.
  • HCI-PRIORS-MLH1.txt.txt was searched for c.1897-7C>T and p.?; no exact row was found, and the index defines that table for missense substitutions.
Still missing
  • No exact c.1897-7C>T or p.? entry was found in HCI-PRIORS-MLH1.txt.txt; that governing lookup is limited to missense substitutions and is not applicable to this intronic variant.
Sources
cspec ↗spliceai ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 2.081e-05, below the VCEP BA1 threshold of 0.001 (0.1%). Details ▾Hide ▴
Reasoning

The MLH1 VCEP defines BA1 as a gnomAD v4 Grpmax filtering allele frequency of at least 0.001 (0.1%), with founder pathogenic variants excluded. The gnomAD v4.1 record reports grpmax FAF 0.00002081 (2.081e-05), far below 0.001; no founder exception is identified in the available evidence. The governing VCEP pilot-variant file was searched for c.1897-7C>T and p.? and contained no matching row.

VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • ClinGen InSiGHT MLH1 specification v2.0, BA1 rule: gnomAD v4 Grpmax filtering allele frequency >=0.001 (0.1%) and variant excluded as founder pathogenic variant.
  • gnomAD v4.1: variant 3-37048510-C-T; grpmax FAF=2.081e-05; total AF=2.3610403489369106e-05; 38/1609460 alleles; homozygotes=0.
  • VCEP-pilot-variants---MMR.xlsx, Sheet1: searches for c.1897-7C>T and p.? returned no matching row.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 2.081e-05, below the VCEP BS1 lower threshold of 0.0001. Details ▾Hide ▴
Reasoning

The MLH1 VCEP defines BS1 as a gnomAD v4 Grpmax filtering allele frequency of at least 0.0001 and below 0.001 (0.01-0.1%), with founder pathogenic variants excluded. The gnomAD v4.1 grpmax FAF is 0.00002081 (2.081e-05), below the lower BS1 boundary, so BS1 is not met. The governing VCEP pilot-variant file was searched for c.1897-7C>T and p.? and contained no matching row.

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
  • ClinGen InSiGHT MLH1 specification v2.0, BS1 rule: gnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001 (0.01-0.1%) and variant excluded as founder pathogenic variant.
  • gnomAD v4.1: variant 3-37048510-C-T; grpmax FAF=2.081e-05; total AF=2.3610403489369106e-05; 38/1609460 alleles; homozygotes=0.
  • VCEP-pilot-variants---MMR.xlsx, Sheet1: searches for c.1897-7C>T and p.? returned no matching row.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 10 · no assessment recorded

PS1 VCEPNot assessed: PS1 requires a qualifying pathogenic same-amino-acid or same-nucleotide splice comparator, but none was identified for c.1897-7C>T. Details ▾Hide ▴
Reasoning

The VCEP permits PS1 Strong for either a same-amino-acid pathogenic missense change or a variant at the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse SpliceAI prediction. This variant has NP_000240.1:p.? and is an intronic c.1897-7C>T change; SpliceAI max delta is 0.099, but no qualifying same-nucleotide confirmed Pathogenic splice comparator was identified in the case evidence. The governing MMR-Functional-domains.pdf file was searched for c.1897-7C>T, NP_000240.1:p.?, p.?, and residue/genomic notation, with no entry. Therefore the comparator-dependent PS1 rule cannot be evaluated.

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). ... 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
  • VCEP PS1 rule: same-amino-acid change requires a different nucleotide change previously established by this VCEP as Pathogenic and not a splice defect; the alternate path requires the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse SpliceAI prediction.
  • The normalized consequence is NP_000240.1:p.? for NM_000249.4:c.1897-7C>T; SpliceAI maximum delta score is 0.099.
  • MMR-Functional-domains.pdf was searched for c.1897-7C>T, NP_000240.1:p.?, p.?, and residue/genomic notation; no entry was found.
Still missing
  • No qualifying confirmed Pathogenic or Likely Pathogenic splice comparator at the same non-canonical nucleotide with a documented SpliceAI comparison was available.
  • MMR-Functional-domains.pdf was searched for c.1897-7C>T, NP_000240.1:p.?, p.?, and residue/genomic notation; no entry was found.
Sources
cspec ↗vcep_mmr_functional_domains ↗
PS2 VCEPNot assessed: no documented de novo result, parental confirmation, qualifying tumor findings, or VCEP de novo point total is available. Details ▾Hide ▴
Reasoning

The MLH1 VCEP evaluates PS2 using de novo probands, confirmation of maternity and paternity, LS-spectrum tumor findings, and assigned de novo points. No case-level record documents a de novo occurrence, parental testing, maternity or paternity confirmation, qualifying tumor findings, or a de novo point total for NM_000249.4:c.1897-7C>T, so PS2 cannot be assessed.

VCEP rule
Proband with a de novo variant with both maternity and paternity confirmed in a case with MMR deficient LS spectrum tumor; the VCEP assigns de novo points according to tumor and parental-confirmation evidence.
Evidence considered
  • No case-level record documents a de novo occurrence, parental testing, maternity or paternity confirmation, or qualifying LS-spectrum tumor for NM_000249.4:c.1897-7C>T.
Still missing
  • Documented proband-level de novo status for NM_000249.4:c.1897-7C>T
  • Maternity and paternity confirmation
  • LS-spectrum tumor type and MSI/IHC/methylation results, if available
  • VCEP de novo point total
Sources
cspec ↗
PS3 VCEPNot assessed: no variant-specific calibrated functional odds, MMR assay readout, or patient RNA expression result is available for c.1897-7C>T. Details ▾Hide ▴
Reasoning

The VCEP permits PS3 from calibrated functional assays with functional odds for pathogenicity above 18.7, between 4.3 and 18.7, or between 2.08 and 4.3, and permits moderate PS3 for an MMR function defect following the functional-assay flowchart or complete loss of variant-allele expression below 10% of wild type. The case contains no variant-specific calibrated functional-odds result, functional-assay readout, or patient RNA expression result for NM_000249.4:c.1897-7C>T. The governing Functional-assay-SVI-documentation-MMR.xlsx table contains no entry for c.1897-7C>T or p.?; the Functional-assay-flowchart.pdf text contains no entry for c.1897-7C>T or p.?; therefore PS3 cannot be assigned.

Evidence considered
  • The CSPEC PS3 entry defines calibrated functional-assay odds thresholds and the MMR function-defect/monoallelic-expression pathways, but the case has no qualifying variant-specific result.
  • Functional-assay-SVI-documentation-MMR.xlsx, sheet 'MMR assays': validated assay rows list assay controls and assay-level thresholds, but no row identifies c.1897-7C>T or p.?.
  • Functional-assay-flowchart.pdf: searched full converted text for c.1897-7C>T and p.?; no variant-specific entry or result was present.
Still missing
  • No entry for c.1897-7C>T or p.? was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
  • No entry for c.1897-7C>T or p.? was found in Functional-assay-flowchart.pdf.txt.
  • No variant-specific calibrated functional-odds result, MMR function assay readout, or patient RNA expression measurement is available in the case evidence.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗PMID:29887214 ↗
PM3 VCEPNot assessed: no documented second pathogenic MLH1 allele or phase, and gnomAD v4.1 grpmax 0.00002081 exceeds the PM2 threshold of <0.00002. Details ▾Hide ▴
Reasoning

The MLH1 VCEP requires co-occurrence with a known pathogenic or likely pathogenic variant in the same gene in a patient with clinical features consistent with CMMRD, and for MLH1 also requires PM2_Supporting. The available case evidence does not document a second pathogenic/likely pathogenic MLH1 variant, its phase, or CMMRD features. In addition, gnomAD v4.1 reports a grpmax filtering allele frequency of 0.00002081, which is above the VCEP PM2 threshold of <0.00002, so the PM2_Supporting prerequisite is not met. PM3 therefore cannot be evaluated under the VCEP rule.

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 as per Aronson et al 2022 - Refer to “Table for CMMRD diagnosis.pdf”. For MLH1 variants - the variant has to meet PM2_Supporting criteria. ... Pathogenic/Likely Pathogenic in trans: 1.0 point; ... Pathogenic/Likely Pathogenic - phase unknown: 0.5 points
Evidence considered
  • The VCEP PM3 entry requires co-occurrence with a known pathogenic/likely pathogenic variant in the same gene in a patient with clinical features consistent with CMMRD, and requires MLH1 variants to meet PM2_Supporting.
  • No case evidence documents a second pathogenic or likely pathogenic MLH1 variant, phase, or CMMRD phenotype for NM_000249.4:c.1897-7C>T.
  • gnomAD v4.1: grpmax filtering allele frequency = 0.00002081 (2.081e-05), compared with the VCEP PM2 rule requiring <0.00002.
Still missing
  • Documented co-occurring pathogenic or likely pathogenic MLH1 variant
  • Phase of the two MLH1 variants
  • Clinical features sufficient to establish CMMRD under the VCEP table
  • A PM2_Supporting-qualifying population frequency for the assessed variant
Sources
cspec ↗gnomad_v4 ↗
PP1 VCEPNot assessed: no pedigree segregation data, informative meioses, family count, or combined Bayes Likelihood Ratio is available. Details ▾Hide ▴
Reasoning

The MLH1 VCEP requires co-segregation in pedigrees with a combined Bayes Likelihood Ratio above a specified threshold, with Strong evidence additionally requiring at least two families. No pedigree, relative genotype or phenotype data, informative meioses, family count, or combined Bayes Likelihood Ratio is available for this variant, so PP1 cannot be assessed.

VCEP rule
Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >2.08 and <=4.3.
Evidence considered
  • No case-level pedigree, relative genotype or phenotype data, informative meioses, family count, or combined Bayes Likelihood Ratio was available for this variant.
Still missing
  • Pedigree with relative disease status and variant genotypes
  • Number of informative families and meioses
  • Combined Bayes Likelihood Ratio
Sources
cspec ↗
PP4 VCEPNot assessed: no patient-specific MSI-H tumor, MLH1-consistent protein loss, or promoter-methylation exclusion is available to satisfy the PP4 supporting rule. Details ▾Hide ▴
Reasoning

PP4 is applicable, but the available case evidence does not provide patient-specific CRC or endometrial MSI-H tumor results, MMR immunohistochemistry loss consistent with MLH1, or MLH1 promoter-methylation exclusion. The CMMRD scoring table is for CMMRD/PM3 assessment and does not contain this variant; the pilot-variant table also has no row for c.1897-7C>T or p.?. Therefore the VCEP PP4 supporting rule cannot be evaluated.

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. For _MLH1_ variants, _MLH1_ promoter methylation is to be excluded in the tumor.
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, with MLH1 promoter methylation excluded for MLH1 variants.
  • Table-for-CMMRD-diagnosis.pdf was consulted in full; it provides CMMRD scoring features and states that >=3 points meets PM3 criteria, but contains no row for this variant.
  • VCEP-pilot-variants---MMR.xlsx was consulted in full; it contains precedent rows for other MMR variants, but no row for c.1897-7C>T or p.?
Still missing
  • Patient-specific CRC or endometrial MSI-H testing and/or tumor-genome results are not available.
  • Patient-specific MMR immunohistochemistry results consistent with MLH1 are not available.
  • Patient-specific exclusion of MLH1 promoter methylation is not available.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis ↗vcep_vcep_pilot_variants_mmr ↗PMID:20301390 ↗PMID:22167527 ↗PMID:23408351 ↗PMID:24493721 ↗PMID:31302137 ↗
BS2 VCEPNot assessed: no confirmed in-trans co-occurrence, phase, cancer-age, or CMMRD information is available for BS2. Details ▾Hide ▴
Reasoning

The MLH1 VCEP BS2 rule requires confirmed co-occurrence in trans with a known pathogenic sequence variant in the same gene, an appropriate cancer age context, no CMMRD manifestations, and parental or offspring testing to confirm phase. No case-level co-occurrence, phase, cancer-age, or CMMRD information is available for this variant.

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​d​), 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
  • ClinGen InSiGHT MLH1 specification v2.0, BS2 requires co-occurrence in trans with a known pathogenic sequence variant, qualifying cancer age, no CMMRD manifestations, and parental or offspring testing for phase confirmation.
Still missing
  • No case-level co-occurrence and phase data are available to evaluate the VCEP BS2 rule.
Sources
cspec ↗
BS3 VCEPNot assessed: no variant-specific calibrated odds or NMD-inhibited protein/mRNA assay result demonstrates proficient function for c.1897-7C>T. Details ▾Hide ▴
Reasoning

The VCEP permits BS3 Strong for calibrated functional odds for pathogenicity at or below 0.05, or for an intronic variant with no associated mRNA aberration demonstrated by laboratory assays with nonsense-mediated-decay inhibition; BS3 Supporting requires calibrated odds above 0.05 and at or below 0.48 or variant-specific proficient protein and mRNA-based assays under the flowchart. The case provides no variant-specific calibrated odds, protein-function result, or NMD-inhibited mRNA assay result for NM_000249.4:c.1897-7C>T. The governing Functional-assay-SVI-documentation-MMR.xlsx table contains no entry for c.1897-7C>T or p.?; the Functional-assay-flowchart.pdf text contains no entry for c.1897-7C>T or p.?; therefore BS3 cannot be assigned.

Evidence considered
  • The CSPEC BS3 entry requires calibrated functional odds or variant-specific proficient protein/mRNA evidence, including NMD-inhibited mRNA testing for the intronic no-aberration pathway; no such result is available.
  • Functional-assay-SVI-documentation-MMR.xlsx, sheet 'MMR assays': validated assay rows list assay controls and assay-level thresholds, but no row identifies c.1897-7C>T or p.?.
  • Functional-assay-flowchart.pdf: searched full converted text for c.1897-7C>T and p.?; no variant-specific entry or result was present.
Still missing
  • No entry for c.1897-7C>T or p.? was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
  • No entry for c.1897-7C>T or p.? was found in Functional-assay-flowchart.pdf.txt.
  • No variant-specific calibrated functional-odds result, proficient protein assay, or NMD-inhibited mRNA assay result is available in the case evidence.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗PMID:29887214 ↗
BS4 VCEPNot assessed: no non-segregation pedigree data, informative meioses, or combined Bayes Likelihood Ratio is available. Details ▾Hide ▴
Reasoning

The MLH1 VCEP requires lack of co-segregation evaluated with a combined Bayes Likelihood Ratio, with Strong evidence below 0.05 and Supporting evidence above 0.05 through 0.48. No non-segregating affected relatives, pedigree, informative meioses, or combined Bayes Likelihood Ratio is available for this variant, so BS4 cannot be assessed.

VCEP rule
Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio <0.05, or >0.05 and <=0.48.
Evidence considered
  • No case-level non-segregation observation, pedigree, relative genotype or phenotype data, informative meioses, or combined Bayes Likelihood Ratio was available for this variant.
Still missing
  • Pedigree showing affected relatives who lack the variant or other non-segregation evidence
  • Informative meioses and family structure
  • Combined Bayes Likelihood Ratio
Sources
cspec ↗
BP5 VCEPNot assessed: no patient-specific MSS, absent or inconsistent MMR-protein loss, BRAF V600E, or MLH1-methylation tumor evidence is available. Details ▾Hide ▴
Reasoning

BP5 is applicable, but no patient-specific tumor evidence is available showing 2 or 3 CRC/endometrial tumors with MSS, no MMR protein loss, inconsistent MMR protein loss in an LS-spectrum tumor, or one BRAF V600E/MLH1-methylated MSI-H tumor with MLH1 loss. The declared pilot table has no row for this variant, so the VCEP BP5 supporting rule cannot be applied.

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 with MSS and/or no loss of MMR protein expression and/or an LS-spectrum tumor with MMR-protein loss inconsistent with the gene demonstrating genetic variation, or 1 BRAF V600E in colon cancer/MLH1 methylation in an LS-spectrum tumor with MSI-H and MLH1 loss.
  • VCEP-pilot-variants---MMR.xlsx was consulted in full; it contains BP5 precedent rows for other variants, but no row for c.1897-7C>T or p.?
Still missing
  • Patient-specific tumor MSI status, MMR protein expression, BRAF V600E status, and MLH1 promoter-methylation results are not available.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_vcep_pilot_variants_mmr ↗PMID:20301390 ↗PMID:22167527 ↗PMID:23408351 ↗PMID:24493721 ↗PMID:31302137 ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1897-7C>T is a non-canonical intronic variant outside the VCEP's named PVS1 classes, with no RNA evidence of a loss-of-function splice consequence. Details ▾Hide ▴
Reasoning

NM_000249.4:c.1897-7C>T is an intronic non-canonical splice variant in MLH1 exon 16i, annotated as NP_000240.1:p.?, with no patient-derived RNA result demonstrating a splice aberration, loss of full-length transcript, premature stop codon, or functional-domain-disrupting in-frame deletion. The governing MLH1 VCEP PVS1 rule names nonsense/frameshift variants, large genomic alterations, IVS±1/IVS±2 variants, confirmed patient-RNA splicing aberrations, and initiation-codon variants; c.1897-7C>T is outside those named PVS1 classes. The available SpliceAI maximum delta score is 0.099, but that computational result does not place this variant within the VCEP PVS1 applicability scope.

VCEP rule
Variants at IVS±1 or IVS±2​<sup>a,c</sup> where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD.
Evidence considered
  • The case annotation records NM_000249.4:c.1897-7C>T, NP_000240.1:p.?, and affected exon 16i.
  • The case evidence records SpliceAI DS_AG 0.099 and maximum delta score 0.099; this is computational evidence only and does not establish the VCEP's required patient-RNA consequence for a non-canonical splice variant.
  • PVS1_DecisionTree_MMR.pdf was searched for c.1897-7C>T and p.?; no matching variant entry was found.
  • VCEP-pilot-variants---MMR.xlsx was searched for c.1897-7C>T and p.?; no matching variant entry was found.
Still missing
  • PVS1_DecisionTree_MMR.pdf: no entry for c.1897-7C>T or p.?.
  • VCEP-pilot-variants---MMR.xlsx: no entry for c.1897-7C>T or p.?.
  • No patient-derived RNA assay result is available to demonstrate a confirmed aberrant transcript for this non-canonical splice variant.
Sources
cspec ↗pvs1_variant_assessmentvcep_pvs1_decisiontree_mmr ↗
PS4 VCEPNot applicable: the MLH1 VCEP excludes PS4 from MMR classification because tumor IHC evidence is handled through PP4 rather than proband counting. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks PS4 as not applicable because tumor IHC data are available for variant classification through PP4; PS4 is not used for MMR variant classification using proband counting. The ON-RECORD files were searched for c.1897-7C>T and p.?; neither Table-for-CMMRD-diagnosis.pdf nor VCEP-pilot-variants---MMR.xlsx contains this variant.

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 MLH1 CSPEC PS4 entry 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.
  • The two declared ON-RECORD files were searched for c.1897-7C>T and p.?; no exact variant row was found.
Still missing
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗PMID:20301390 ↗PMID:22167527 ↗PMID:23408351 ↗PMID:24493721 ↗PMID:31302137 ↗
PM1 VCEPNot applicable: the MLH1 VCEP explicitly marks PM1 not applicable, and its authoritative domain_tables entry is empty. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks PM1 Not applicable. The authoritative vcep_materials.json domain_tables entry for MLH1 is empty, and the governing MMR-Functional-domains.pdf was searched for c.1897-7C>T, NP_000240.1:p.?, p.?, and residue/genomic notation without an entry.

VCEP rule
Not applicable
Evidence considered
  • The MLH1 VCEP CSPEC entry for PM1 states applicability: Not applicable.
  • vcep_materials.json has domain_tables: {} for MLH1, so no authoritative MLH1 critical-domain entry is available to evaluate.
  • MMR-Functional-domains.pdf was searched for c.1897-7C>T, NP_000240.1:p.?, p.?, and residue/genomic notation; no entry was found.
Sources
cspec ↗vcep_mmr_functional_domains ↗
PM4 VCEPNot applicable: the MLH1 VCEP explicitly marks PM4 Not Applicable, and this variant has no defined protein-length change beyond p.?. Details ▾Hide ▴
Reasoning

The MLH1 VCEP Version 2.0 CSPEC marks PM4 as Not Applicable. No protein-length change or other PM4 assessment can therefore activate this criterion under the governing framework; the variant is annotated as p.? rather than a defined protein-length change.

VCEP rule
Not Applicable
Evidence considered
  • The MLH1 Version 2.0 CSPEC entry for PM4 states applicability: Not Applicable.
  • The case annotation is NP_000240.1:p.?, with no defined amino-acid-length change.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires a missense change at a defined amino-acid residue, while c.1897-7C>T has protein consequence p.? . Details ▾Hide ▴
Reasoning

The VCEP PM5 rule applies to a missense change at an amino acid residue compared with a different VCEP-classified missense change. This variant has an unknown consequence and NP_000240.1:p.?, so it is not a missense protein-level change eligible for PM5.

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.
Evidence considered
  • VCEP PM5 requires a missense change at an amino-acid residue and a different missense comparator classified by the VCEP on the protein level.
  • The normalized protein consequence is NP_000240.1:p.? and the consequence class is unknown; no amino-acid residue is defined.
Sources
cspec ↗
PM6 VCEPNot applicable: the MLH1 VCEP marks PM6 Not Applicable and directs de novo assessment to PS2. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks PM6 as not applicable and directs de novo assessment to PS2; PM6 is therefore not used independently.

VCEP rule
Not Applicable
Evidence considered
  • The VCEP PM6 entry states applicability is Not Applicable and directs assessment to PS2.
Sources
cspec ↗
PP2 VCEPNot applicable: the MLH1 VCEP explicitly marks PP2 not applicable for this specification. Details ▾Hide ▴
Reasoning

The MLH1 VCEP explicitly marks PP2 Not applicable; no gene-level missense-mechanism assessment is permitted under this specification.

VCEP rule
Not applicable
Evidence considered
  • The MLH1 VCEP CSPEC entry for PP2 states applicability: Not applicable and instructs that the criterion does not apply.
Sources
cspec ↗
PP5 VCEPNot applicable: the MLH1 VCEP prohibits PP5 regardless of the available external classifications or literature. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The ON-RECORD files were searched for c.1897-7C>T and p.?; neither declared file contains this variant.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The MLH1 CSPEC PP5 entry states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • The two declared ON-RECORD files were searched for c.1897-7C>T and p.?; no exact variant row was found.
Still missing
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗PMID:20301390 ↗PMID:22167527 ↗PMID:23408351 ↗PMID:24493721 ↗PMID:31302137 ↗
BP1 VCEPNot applicable: the MLH1 VCEP explicitly marks BP1 not applicable for this specification. Details ▾Hide ▴
Reasoning

The MLH1 VCEP explicitly marks BP1 Not applicable; no benign-missense-mechanism assessment is permitted under this specification.

VCEP rule
Not applicable
Evidence considered
  • The MLH1 VCEP CSPEC entry for BP1 states applicability: Not applicable.
Sources
cspec ↗
BP2 VCEPNot applicable: the MLH1 VCEP explicitly marks BP2 as not applicable. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks BP2 as not applicable. No BP2 evidence can be assigned under this VCEP specification.

VCEP rule
Not Applicable
Evidence considered
  • The VCEP CSPEC entry for BP2 states: applicability = Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the MLH1 VCEP explicitly marks BP3 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The MLH1 VCEP Version 2.0 CSPEC marks BP3 as Not Applicable. Repeat-region context therefore cannot be used to assign BP3 under this governing framework, regardless of the intronic location of NM_000249.4:c.1897-7C>T.

VCEP rule
Not Applicable
Evidence considered
  • The MLH1 Version 2.0 CSPEC entry for BP3 states applicability: Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the MLH1 VCEP prohibits BP6 regardless of the available external benign classifications or literature. Details ▾Hide ▴
Reasoning

The MLH1 VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The ON-RECORD files were searched for c.1897-7C>T and p.?; neither declared file contains this variant.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The MLH1 CSPEC BP6 entry states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • The two declared ON-RECORD files were searched for c.1897-7C>T and p.?; no exact variant row was found.
Still missing
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/Table-for-CMMRD-diagnosis.pdf.txt.
  • No entry for c.1897-7C>T or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/MLH1/fulltext/VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗PMID:20301390 ↗PMID:22167527 ↗PMID:23408351 ↗PMID:24493721 ↗PMID:31302137 ↗
BP7 N/ANot applicable: c.1897-7C>T lies 7 bases upstream of the exon, not at or beyond the VCEP BP7 boundary of -21/+7. Details ▾Hide ▴
Reasoning

BP7 is not applicable because the VCEP limits it to synonymous or intronic variants at or beyond the -21/+7 positions relative to the exon boundaries. c.1897-7C>T is 7 bases upstream of the exon, within the -21/+7 interval and therefore outside the stated BP7 scope.

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
  • The exact HGVS location is NM_000249.4:c.1897-7C>T, an intronic position 7 bases upstream of the exon.
  • Because -7 is within the VCEP-defined -21/+7 interval, the variant does not satisfy the BP7 location requirement.
Sources
cspec ↗

Identifiers

Gene
MLH1
Transcript
NM_000249.4
Coding (HGVS c.)
NM_000249.4:c.1897-7C>T
Protein (HGVS p.)
NP_000240.1:p.?
GRCh38
chr3:37048510 C>T
GRCh37
chr3:37090001 C>T
Location and type
Intron 16 · unknown
ClinVar
405407

Gene diagram

Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.4. Select a row to find it on the plot.

MLH1NM_000249.4
Fetching transcript structure from UCSC…
gnomAD v4.1 38 / 1,609,460 alleles AF 2.36e-05 · 0 homozygotes · FAF 2.08e-05
gnomAD v2.1 1 / 251,320 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.4e-05 · 38 / 1,609,460 alleles · 0 hom · FAF 2.1e-05
Remaining individuals3 / 62,340 4.8e-05
European (non-Finnish)34 / 1,176,042 2.9e-05
African/African American1 / 74,766 1.3e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 4e-06 · 1 / 251,320 alleles · 0 hom
African/African American1 / 16,256 6.2e-05
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.36104e-05; MAF= 0.00236%, 38/1609460 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.81232e-05; MAF= 0.00481%, 3/62340 alleles, homozygotes = 0); grpmax FAF= 2.081e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -32 bp
0.005
SpliceAI acceptor gainat +4 bp
0.099
SpliceAI donor lossat -198 bp
0.001
SpliceAI donor gainat +130 bp
0.001
Pangolin splice lossmagnitude shown
-0.085
Pangolin splice gain
0.047

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingVCEPMet at Supporting: SpliceAI maximum delta score 0.099 meets the VCEP BP4 no-impact cutoff of <=0.1 for intronic variants. Details ▾Hide ▴
Reasoning

The variant is intronic, making the VCEP intronic/synonymous SpliceAI path applicable. SpliceAI predicts no splicing impact with a maximum delta score of 0.099, which meets the VCEP cutoff of <=0.1; BP4 is therefore met at Supporting strength. The HCI-PRIORS-MLH1.txt.txt file was searched for c.1897-7C>T and p.? and contains no exact entry, but its governing index limits that lookup to missense substitutions.

VCEP rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023
Evidence considered
  • NM_000249.4:c.1897-7C>T is an intronic variant, so the VCEP intronic SpliceAI path applies.
  • SpliceAI scores for the exact variant are DS_AG 0.099, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.001; maximum delta score = 0.099, at or below the VCEP BP4 cutoff of 0.1.
  • HCI-PRIORS-MLH1.txt.txt was searched for c.1897-7C>T and p.?; no exact row was found, and the index defines that table for missense substitutions.
Still missing
  • No exact c.1897-7C>T or p.? entry was found in HCI-PRIORS-MLH1.txt.txt; that governing lookup is limited to missense substitutions and is not applicable to this intronic variant.
Sources
cspec ↗spliceai ↗
PP3 VCEPNot met: SpliceAI maximum delta score 0.099 is below the VCEP PP3 threshold of 0.2 for a predicted non-canonical splice defect. Details ▾Hide ▴
Reasoning

The variant is a non-canonical intronic substitution, so the applicable VCEP PP3 path is the SpliceAI predicted-splice-defect path. SpliceAI reports a maximum delta score of 0.099 (DS_AG 0.099; all other DS values <=0.005), which is below the VCEP threshold of >=0.2. The HCI-PRIORS-MLH1.txt.txt file was searched for c.1897-7C>T and p.? and contains no exact entry; its missense-only lookup path therefore does not apply to this intronic variant.

VCEP rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.
Evidence considered
  • NM_000249.4:c.1897-7C>T is intronic and non-canonical; the protein annotation is NP_000240.1:p.?.
  • SpliceAI scores for the exact variant are DS_AG 0.099, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.001; maximum delta score = 0.099, below the VCEP PP3 threshold of >=0.2.
  • HCI-PRIORS-MLH1.txt.txt was searched for c.1897-7C>T and p.?; no exact row was found, and the index defines that table for missense substitutions.
Still missing
  • No exact c.1897-7C>T or p.? entry was found in HCI-PRIORS-MLH1.txt.txt; that governing lookup is limited to missense substitutions and is not applicable to this intronic variant.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: c.1897-7C>T lies 7 bases upstream of the exon, not at or beyond the VCEP BP7 boundary of -21/+7. Details ▾Hide ▴
Reasoning

BP7 is not applicable because the VCEP limits it to synonymous or intronic variants at or beyond the -21/+7 positions relative to the exon boundaries. c.1897-7C>T is 7 bases upstream of the exon, within the -21/+7 interval and therefore outside the stated BP7 scope.

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
  • The exact HGVS location is NM_000249.4:c.1897-7C>T, an intronic position 7 bases upstream of the exon.
  • Because -7 is within the VCEP-defined -21/+7 interval, the variant does not satisfy the BP7 location requirement.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

9 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

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.
    Shirts BH et al. · 2018
    The paper does not explicitly mention MLH1 c.1897-7C>T or the protein notation NP_000240.1:p.?. It evaluates somatic mismatch-repair variants and reports biological evidence relevant to splice-disrupting variants, but provides no variant-specific functional assay result for this variant.
    Does not name this variant
    PMID 29887214 ↗
    Quoted passage
    Our data suggest that information obtained from tumor samples provides independent biological evidence of clinically meaningful splice disruptions.

    Discussion, paragraph beginning "In the past, in silico predictions of splice alterations..."

  • Lynch Syndrome.
    Adam MP et al. · 1993
    The source was listed as a literature lead for PS4 and PP5, but no full text or extracted variant-level finding is available; it cannot support either criterion.
    Does not name this variant
    PMID 20301390 ↗
  • Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.
    The paper does not mention MLH1 c.1897-7C>T or provide variant-level clinical, tumor, segregation, or population data; it is a general Lynch syndrome evaluation guideline.
    Does not name this variant
    PMID 22167527 ↗
    Quoted passage
    Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for ~3% of colorectal cancers

    Introduction; Germline Genetic Testing section

  • Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.
    The paper does not mention MLH1 c.1897-7C>T or a corresponding protein change and provides only gene-level Lynch syndrome and MSI background, not variant-specific phenotype evidence.
    Does not name this variant
    PMID 23408351 ↗
    Quoted passage
    An MMR gene defect leads through loss of the corresponding normal alleles in the tumours of carriers to loss of MMR function and results in an accumulation of mutations in (coding and non-coding) microsatellites in such tumours (so-called microsatellites instability; MSI).

    Short update on LS

  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    Lu KH et al. · 2014
    The paper does not report MLH1 c.1897-7C>T or its protein consequence; it gives general criteria for evaluating mismatch-repair-deficient colorectal cancer after excluding MLH1 promoter hypermethylation and BRAF mutation.
    Does not name this variant
    PMID 24493721 ↗
    Quoted passage
    Colorectal cancer demonstrating mismatch repair deficiency (via tumor studies including microsatellite instability analysis and/or immunohistochemistry, excluding known somatic causes including hypermethylation of MLH1 promoter and somatic BRAF mutation)

    Table 2

  • Lynch Syndrome in Urologic Malignancies - What Does the Urologist Need to Know?
    The paper does not mention MLH1 c.1897-7C>T or p.? and reports only gene-level MLH1 involvement and cancer rates, not variant-specific phenotype or alternate-molecular-basis evidence.
    Does not name this variant
    PMID 31302137 ↗
    Quoted passage
    LS-associated cancers develop because of autosomal dominant heterozygous germline mutations in one of the four main MMR genes. These include the: (1) mutL homologue 1 (MLH1), (2) mutS homologue 2 (MSH2), or 6 (MSH6) or (4) post-meiotic segregation increased 2 (PMS2).

    Introduction, paragraph 3; gene-level mutation rates in sections 5.1 UTUC, 5.2 Bladder cancer, and 5.3 Prostate cancer

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 38 / 1,609,460 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.099 Open source ↗
ClinVar 7 Likely benign · 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC 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= 2.36104e-05; MAF= 0.00236%, 38/1609460 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.81232e-05; MAF= 0.00481%, 3/62340 alleles, homozygotes = 0); grpmax FAF= 2.081e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97899e-06; MAF= 0.00040%, 1/251320 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 405407)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).