About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.551C>G, p.(Ser184Ter)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_000249.3:c.551C>G is a nonsense variant that introduces a premature termination codon at codon 184 (p.Ser184Ter), well before codon 753 of MLH1. Under the InSiGHT VCEP v2.0 PVS1 rules, nonsense variants introducing a PTC at or before codon 753 qualify for PVS1_VeryStrong. Loss of function is an established disease mechanism for MLH1 in Lynch syndrome.
PM2Supporting
PM2 · supporting
NM_000249.3:c.551C>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under the InSiGHT VCEP v2.0, PM2_Supporting is met when the variant allele frequency is <0.00002 (<1 in 50,000 alleles) in gnomAD v4, which is satisfied by complete absence.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000249.3:c.551C>G (p.Ser184Ter) is a nonsense variant that introduces a premature termination codon at codon 184 of MLH1, well before the VCEP threshold of codon 753, meeting PVS1_VeryStrong.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2_Supporting under the InSiGHT VCEP threshold of <0.00002 allele frequency.
ClinVar reports this variant as Pathogenic with 3 clinical laboratory submissions, classified as criteria provided, single submitter. However, under the InSiGHT VCEP, PP5 and BP6 are not applicable, and ClinVar classification alone does not independently satisfy other criteria.
No variant-specific functional studies, patient phenotype data, co-segregation data, or de novo observations were identified in the available literature or case materials.
No criteria match.
Met · 2
PVS1 Very strongNM_000249.3:c.551C>G is a nonsense variant that introduces a premature termination codon at codon 184 (p.Ser184Ter), well before codon 753 of MLH1. Under the InSiGHT VCEP v2.0 PVS1 rules, nonsense variants introducing a PTC at or before codon 753 qualify for PVS1_VeryStrong. Loss of function is an established disease mechanism for MLH1 in Lynch syndrome. Details ▾Hide ▴
Evidence considered
- Nonsense variant (C>G) at codon 184 creates p.(Ser184Ter)
- PTC located at codon 184
- well before the VCEP threshold of codon 753
- MLH1 loss of function is an established mechanism for Lynch syndrome
Sources
PM2 SupportingNM_000249.3:c.551C>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under the InSiGHT VCEP v2.0, PM2_Supporting is met when the variant allele frequency is <0.00002 (<1 in 50,000 alleles) in gnomAD v4, which is satisfied by complete absence. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 10 · evaluated, threshold not reached
PS2 No de novo observations have been reported for this variant in the available evidence. No publications, ClinVar submissions, or database entries document a confirmed de novo occurrence. Details ▾Hide ▴
Still missing
- No de novo data available in case materials
PS3 No variant-specific functional assay data is available for NM_000249.3:c.551C>G in the calibrated MMR functional assay documentation or the literature. The variant is a nonsense change predicted to cause loss of function via NMD, but this is captured under PVS1; PS3 requires experimental functional evidence which is absent. OncoKB lists the variant as Likely Oncogenic / Likely Loss-of-function but provides no associated PMIDs with functional data. Details ▾Hide ▴
Evidence considered
- OncoKB annotation: Likely Loss-of-function / Likely Oncogenic (no variant-specific functional PMIDs)
Still missing
- No calibrated functional assay data for this nonsense variant
- No variant-specific functional studies identified in literature
Sources
PP1 No co-segregation data is available for this variant in the case materials. No pedigrees or segregation analysis were provided or identified in the literature. Details ▾Hide ▴
Still missing
- No co-segregation or family pedigree data available
PP4 No patient-specific phenotype data (MSI status, IHC, tumor type) is available for this variant in the case materials. PP4 under the InSiGHT VCEP requires at least one CRC/Endometrial MSI-H tumor and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Still missing
- No MSI/IHC tumor data available
- No patient phenotype or family history data
BA1 BA1 under the InSiGHT VCEP v2.0 requires a gnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%). This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The frequency threshold for BA1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- allele frequency is 0
- well below the BA1 threshold of ≥ 0.1%
Sources
BS1 BS1 under the InSiGHT VCEP v2.0 requires a gnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) with exclusion of founder pathogenic variants. This variant is absent from all gnomAD datasets. The frequency threshold for BS1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- allele frequency is 0
- below the BS1 threshold of ≥ 0.01%
Sources
BS2 BS2 under the InSiGHT VCEP v2.0 requires co-occurrence in trans with a known pathogenic variant in a patient with colorectal cancer after age 45 without CMMRD features. No such co-occurrence data is available for this variant. Details ▾Hide ▴
Still missing
- No co-occurrence (in trans) data available
BS3 No variant-specific functional data demonstrating a benign or normal functional effect is available. The calibrated MMR functional assay documentation does not include this variant, and no publications report functional studies showing normal MMR function for p.Ser184Ter. Details ▾Hide ▴
Still missing
- No functional data demonstrating normal protein function
BS4 No co-segregation or lack-of-segregation data is available for this variant. No family pedigrees with Bayes likelihood ratios are present in the case materials. Details ▾Hide ▴
Still missing
- No co-segregation data available
BP5 No tumor data demonstrating MSS status, retained MMR protein expression, or an alternate molecular basis for disease is available for this variant. BP5 under the InSiGHT VCEP requires tumor evidence inconsistent with pathogenic MMR deficiency. Details ▾Hide ▴
Still missing
- No tumor MSS/IHC data available
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 under the InSiGHT VCEP is defined for missense substitutions that encode the same amino acid change with a different nucleotide change, or for splice variants affecting the same non-canonical splice nucleotide. This variant is a nonsense substitution (p.Ser184Ter), not a missense change, and does not meet the VCEP PS1 criteria. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP PS1 rules apply only to missense substitutions or splice variants
Sources
PS4 VCEPPS4 is not applicable under the InSiGHT VCEP v2.0. The VCEP 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.' Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks PS4 as Not Applicable for MLH1/MMR variant classification
Sources
PM1 VCEPPM1 is not applicable under the InSiGHT VCEP v2.0. The VCEP states: '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.' Details ▾Hide ▴
PM5 N/APM5 under the InSiGHT VCEP v2.0 is defined for missense changes at an amino acid residue where a different missense change has been classified as pathogenic/likely pathogenic. NM_000249.3:c.551C>G is a nonsense variant (p.Ser184Ter), not a missense change, and therefore does not satisfy the VCEP PM5 criteria. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP PM5 rules apply only to missense substitutions at the same residue
Sources
PM6 VCEPPM6 is not applicable under the InSiGHT VCEP v2.0. The VCEP directs users to use PS2 for de novo evidence instead (instructions: 'Please see PS2'). Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks PM6 as Not Applicable
- PS2 is used for de novo evidence
Sources
PP2 VCEPPP2 is not applicable under the InSiGHT VCEP v2.0. The VCEP states: 'Missense variant in a gene with low rate of benign missense changes does not apply.' Additionally, this variant is a nonsense change, not a missense. Details ▾Hide ▴
PP3 N/APP3 under the InSiGHT VCEP v2.0 is defined for missense variants (HCI prior probability for pathogenicity) or predicted splice defects for non-canonical splice nucleotides (SpliceAI delta score ≥ 0.2). This variant is a nonsense substitution (p.Ser184Ter) creating a premature termination codon. It is not a missense variant (HCI prior not applicable) and SpliceAI predicts no splice impact (max delta 0.00). The VCEP PP3 rules do not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP PP3 rules apply only to missense (HCI prior) or splice predictions
- SpliceAI max delta score: 0.00 (no splice impact)
- HCI prior: not applicable (nonsense
- not in missense table)
Sources
PP5 VCEPPP5 is not applicable for this VCEP. The InSiGHT VCEP v2.0 states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP1 VCEPBP1 is not applicable under the InSiGHT VCEP v2.0. The VCEP states: 'Missense variant in a gene where only loss of function causes disease is not applicable.' This variant is a nonsense change causing loss of function. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable under the InSiGHT VCEP v2.0. The VCEP states: 'BS2 is used instead.' Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks BP2 as Not Applicable
- BS2 is used for co-occurrence/phase evidence
Sources
BP4 N/ABP4 under the InSiGHT VCEP v2.0 is defined for missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta ≤ 0.1. This variant is a nonsense substitution (p.Ser184Ter) creating a premature termination codon. Neither VCEP BP4 rule applies; SpliceAI delta of 0.00 for a nonsense variant does not constitute evidence of no impact. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP BP4 rules apply only to missense (HCI prior) or intronic/synonymous variants (SpliceAI)
Sources
BP6 VCEPBP6 is not applicable for this VCEP. The InSiGHT VCEP v2.0 states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP7 N/ABP7 under the InSiGHT VCEP v2.0 applies to synonymous (silent) or intronic variants. NM_000249.3:c.551C>G is a nonsense variant (p.Ser184Ter), not a synonymous or intronic change, and therefore does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP BP7 applies only to synonymous or intronic variants
Sources
PS5 N/APS5 is not a defined criterion in the ACMG/AMP 2015 framework, the ClinGen SVI recommendations, or the InSiGHT VCEP v2.0 specifications for MLH1. No evidence can be evaluated under this criterion. Details ▾Hide ▴
Evidence considered
- PS5 is not a recognized ACMG/AMP criterion
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.3
- Coding (HGVS c.)
- NM_000249.3:c.551C>G
- Protein (HGVS p.)
- NP_000240.1:p.(Ser184Ter)
- GRCh38
- chr3:37011825 C>G
- GRCh37
- chr3:37053316 C>G
- ClinVar
- 455446, 90391
Gene diagram
Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.3. Select a row to find it on the plot.
MLH1NM_000249.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MLH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.112
- BayesDel
- 0.660
How the predictions were used
PP3 N/APP3 under the InSiGHT VCEP v2.0 is defined for missense variants (HCI prior probability for pathogenicity) or predicted splice defects for non-canonical splice nucleotides (SpliceAI delta score ≥ 0.2). This variant is a nonsense substitution (p.Ser184Ter) creating a premature termination codon. It is not a missense variant (HCI prior not applicable) and SpliceAI predicts no splice impact (max delta 0.00). The VCEP PP3 rules do not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP PP3 rules apply only to missense (HCI prior) or splice predictions
- SpliceAI max delta score: 0.00 (no splice impact)
- HCI prior: not applicable (nonsense
- not in missense table)
Sources
BP4 N/ABP4 under the InSiGHT VCEP v2.0 is defined for missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta ≤ 0.1. This variant is a nonsense substitution (p.Ser184Ter) creating a premature termination codon. Neither VCEP BP4 rule applies; SpliceAI delta of 0.00 for a nonsense variant does not constitute evidence of no impact. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP BP4 rules apply only to missense (HCI prior) or intronic/synonymous variants (SpliceAI)
Sources
BP7 N/ABP7 under the InSiGHT VCEP v2.0 applies to synonymous (silent) or intronic variants. NM_000249.3:c.551C>G is a nonsense variant (p.Ser184Ter), not a synonymous or intronic change, and therefore does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- VCEP BP7 applies only to synonymous or intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.112. BayesDel score = 0.66.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15713769 ↗Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.Casey G et al. · 2005Describes conversion analysis methodology for mutation detection in MLH1 and MSH2 in colorectal cancer patients. NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
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PMID 10359802 ↗Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.Compares mutator phenotypes in Mlh1- versus Pms2-deficient mice. Gene-level study of MMR deficiency; NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
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PMID 11781295 ↗Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.Functional analysis of hMLH1 missense variants in a human expression system. Focuses on missense variants; NM_000249.3:c.551C>G (nonsense) was not identified in the abstract.Does not name this variant
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PMID 12697830 ↗Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.Investigates MLH1 and PMS2 dimerization and nuclear localization of MutLalpha. NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
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PMID 16216036 ↗Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.Examines MSH2 and MLH1 IHC staining patterns in HNPCC tumors. NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
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PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Thompson BA et al. · 2014Describes the InSiGHT 5-tiered classification scheme applied to 2,360 MMR gene variants. NM_000249.3:c.551C>G was not identified in the abstract, though this variant may be among the classified variants in the full LOVD database.Does not name this variant
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PMID 22167527 ↗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.Joint practice guideline from NSGC and CGA-ICC on identifying individuals at risk for Lynch syndrome. NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes the Sherloc refinement of ACMG-AMP variant classification criteria. NM_000249.3:c.551C>G was not identified in the abstract.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1564688410
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/455446/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37053316-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37011825-C-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37011825-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.3%3Ac.551C…
- OncoKB ↗www.oncokb.org/gene/MLH1/S184*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.551C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 455446)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.112. BayesDel score = 0.66.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.