About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.290A>G, p.(Tyr97Cys)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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 v2.0.0. 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
BA1Stand alone
BA1 · stand alone
This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.0015372 in the South Asian population, which is above the MLH1 VCEP BA1 threshold of 0.001. No founder pathogenic designation was identified in the available evidence.
Recorded classification: Benign
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign; maps to Benign.
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
173 / 1,605,044 alleles
gnomAD v4.1: 173 / 1,605,044 alleles. Recorded AF 0.000107785. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000242661; MAF= 0.02427%, 61/251380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00192735; MAF= 0.19273%, 59/30612 alleles, homozygotes = 0); grpmax FAF= 0.00153368.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 9 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MLH1 c.290A>G (p.Tyr97Cys) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar with conflicting germline interpretations, including uncertain significance, likely benign, and benign submissions.
This variant is present in gnomAD at a South Asian grpmax filtering allele frequency of 0.0015372 in v4.1, which is above the MLH1 VCEP BA1 threshold of 0.001; gnomAD v2.1 also shows elevated South Asian frequency with grpmax FAF 0.00153368.
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL is 0.603 and BayesDel is 0.230019, but no MLH1 VCEP HCI prior probability was identified to support PP3 or BP4 for this missense change.
No criteria match.
Met · 1
BA1 Stand aloneThis variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.0015372 in the South Asian population, which is above the MLH1 VCEP BA1 threshold of 0.001. No founder pathogenic designation was identified in the available evidence. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >= 0.001 and variant is excluded as founder pathogenic variant
Evidence considered
- gnomAD v4.1 joint grpmax FAF = 0.0015372
- Highest observed population = South Asian
Still missing
- Founder pathogenic exclusion was not independently confirmed beyond the available public evidence.
Sources
Not met · 9 · evaluated, threshold not reached
PVS1 This variant is a missense change, p.(Tyr97Cys), and does not fall into the default MLH1 null-variant categories for PVS1. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and no RNA evidence showing loss of full-length transcript was identified. Details ▾Hide ▴
Rule
MLH1 PVS1 for qualifying null or proven splice-loss variants
Evidence considered
- pvs1_variant_assessment classifies this variant outside default generic PVS1 buckets.
- SpliceAI max delta score = 0.01
Still missing
- Variant-specific constitutional RNA evidence would be needed to revisit PVS1 for a splice-mediated loss-of-function mechanism.
Sources
PS1 No previously established MLH1 pathogenic or likely pathogenic variant encoding the same Tyr97Cys amino acid change by a different nucleotide change was identified in the reviewed VCEP materials. Details ▾Hide ▴
Rule
Same amino acid change as a previously established VCEP pathogenic or likely pathogenic variant, depending on strength
Evidence considered
- No same-amino-acid alternate nucleotide match was identified in the reviewed VCEP pilot variants workbook.
Still missing
- Additional external review could be performed if a same-amino-acid alternate nucleotide change is later reported.
Sources
cspec ↗vcep_vcep_pilot_variants_mmr
PS3 No variant-specific calibrated functional assay result showing a damaging MLH1 effect was identified for this missense variant in the reviewed functional assay documentation or curated evidence sources. Details ▾Hide ▴
Rule
Calibrated functional assays with functional odds for pathogenicity >2.08, >4.3, or >18.7 depending on strength
Evidence considered
- No Y97C or c.290A>G entry was identified in the reviewed MMR functional assay documentation workbook.
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Direct review of any exact-variant functional publication
- if one exists
- would be needed to revisit PS3.
Sources
PM2 This variant is not absent or extremely rare in gnomAD v4.1. Its total allele frequency is 0.000107785, which is above the MLH1 VCEP PM2 threshold of less than 0.00002. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency < 0.00002 in gnomAD v4
Evidence considered
- gnomAD v4.1 total AF = 0.000107785
- gnomAD v4.1 South Asian grpmax FAF = 0.0015372
Sources
PM5 No different MLH1 missense variant at Tyr97 established by this VCEP as pathogenic or likely pathogenic on the protein level was identified in the reviewed VCEP materials, so PM5 is not supported. Details ▾Hide ▴
Rule
Different pathogenic or likely pathogenic missense change at the same residue, with PP3 support
Evidence considered
- No qualifying Tyr97 alternate missense variant was identified in the reviewed VCEP pilot variants workbook.
Still missing
- Additional external residue-level review could be performed if new Tyr97 substitutions are reported.
Sources
cspec ↗vcep_vcep_pilot_variants_mmr
PP3 For MLH1 missense variants, PP3 requires an HCI prior probability of pathogenicity above 0.68. No qualifying HCI prior result was identified, SpliceAI does not support a splice effect with a maximum delta score of 0.01, and the available REVEL and BayesDel scores do not independently satisfy the MLH1 VCEP missense PP3 rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability > 0.68 or non-canonical splice variant with SpliceAI >= 0.2
Evidence considered
- SpliceAI max delta score = 0.01
- REVEL score = 0.603
- BayesDel score = 0.230019
- No HCI prior probability was identified in the retrieved evidence.
Still missing
- An HCI prior probability result would be needed for formal PP3 missense evaluation under the MLH1 VCEP rule.
Sources
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 0.0015372, which is above the BS1 range of 0.0001 to less than 0.001 and instead falls into the BA1 range. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >= 0.0001 and < 0.001
Evidence considered
- gnomAD v4.1 joint grpmax FAF = 0.0015372
Sources
BS3 No variant-specific functional study showing retained MLH1 function or normal RNA behavior was identified for this variant in the reviewed functional assay documentation or curated evidence sources. Details ▾Hide ▴
Rule
Calibrated functional odds <= 0.48 or qualifying proficient function depending on strength
Evidence considered
- No Y97C or c.290A>G entry was identified in the reviewed MMR functional assay documentation workbook.
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Direct review of any exact-variant benign functional publication
- if one exists
- would be needed to revisit BS3.
Sources
BP4 For MLH1 missense variants, BP4 requires an HCI prior probability of pathogenicity below 0.11. No qualifying HCI prior result was identified, and although REVEL is 0.603 and BayesDel is 0.230019, those scores do not substitute for the VCEP missense BP4 rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability < 0.11
Evidence considered
- REVEL score = 0.603
- BayesDel score = 0.230019
- No HCI prior probability was identified in the retrieved evidence.
Still missing
- An HCI prior probability result would be needed for formal BP4 evaluation under the MLH1 VCEP rule.
Sources
Not assessed · 7 · no assessment recorded
PS2 No de novo observation with the required parental confirmation and Lynch syndrome tumor context was identified for this variant. Details ▾Hide ▴
Rule
Points-based de novo framework
Evidence considered
- No de novo case-level evidence was identified in the retrieved materials.
Still missing
- Parental testing information was not available.
- Required tumor MSI or IHC context was not available.
Sources
PM3 No evidence was identified that this variant occurs in trans with a pathogenic or likely pathogenic MLH1 variant in an individual meeting CMMRD-based scoring requirements. Details ▾Hide ▴
Rule
Points-based PM3 framework for CMMRD-related observations
Evidence considered
- No in trans co-occurrence data were identified in the retrieved evidence.
Still missing
- Phase information and CMMRD clinical scoring data were not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified, so co-segregation with Lynch syndrome-associated disease could not be evaluated. Details ▾Hide ▴
Rule
Co-segregation with disease using Bayes likelihood ratio thresholds
Evidence considered
- No family segregation evidence was identified in the retrieved materials.
Still missing
- Pedigree-level segregation data were not available.
- A Bayes likelihood ratio could not be calculated.
Sources
PP4 No tumor microsatellite instability, mismatch repair immunohistochemistry, or MLH1 promoter methylation results were identified, so the Lynch syndrome tumor phenotype requirements for PP4 could not be evaluated. Details ▾Hide ▴
Rule
PP4 Supporting/Moderate/Strong requires Lynch syndrome tumor evidence with MLH1 methylation exclusion
Evidence considered
- No case-level tumor phenotype data meeting PP4 requirements were identified.
Still missing
- Tumor MSI or tumor genome results were not available.
- Tumor MMR protein expression results were not available.
- MLH1 promoter methylation exclusion data were not available.
Sources
BS2 No confirmed in trans co-occurrence with a known pathogenic MLH1 variant in an appropriately phenotyped individual without evidence of CMMRD was identified. Details ▾Hide ▴
Rule
Confirmed in trans co-occurrence with a known pathogenic variant in an individual without CMMRD manifestations
Evidence considered
- No qualifying BS2 co-occurrence evidence was identified in the retrieved materials.
Still missing
- Phase confirmation was not available.
- Clinical exclusion of CMMRD was not available.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS4 No non-segregation data were identified, so lack of co-segregation with Lynch syndrome-associated disease could not be evaluated. Details ▾Hide ▴
Rule
Lack of co-segregation using Bayes likelihood ratio thresholds
Evidence considered
- No family non-segregation evidence was identified in the retrieved materials.
Still missing
- Pedigree-level non-segregation data were not available.
- A Bayes likelihood ratio could not be calculated.
Sources
BP5 No tumor evidence showing a molecular profile inconsistent with MLH1-related Lynch syndrome, such as MSS tumors, intact relevant MMR protein expression, or MLH1 methylation/BRAF findings, was identified. Details ▾Hide ▴
Rule
BP5 Supporting/Strong based on inconsistent tumor findings or MLH1 methylation/BRAF evidence
Evidence considered
- No case-level alternate molecular basis evidence was identified.
Still missing
- Tumor MSS or MSI results were not available.
- MMR protein expression data were not available.
- BRAF V600E and MLH1 methylation data were not available.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 N/AThis criterion is not used in the MLH1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MLH1 VCEP marks PS4 as not applicable.
Sources
PM1 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
PM4 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
PM6 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
PP2 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
PP5 N/AThis criterion is not used in the MLH1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MLH1 VCEP marks PP5 as not applicable.
Sources
BP1 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
BP2 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
BP3 N/AThis criterion is not applicable in the MLH1 VCEP framework. Details ▾Hide ▴
BP6 N/AThis criterion is not used in the MLH1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MLH1 VCEP marks BP6 as not applicable.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or qualifying intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant at or beyond -21/+7
Evidence considered
- Variant consequence = missense p.(Tyr97Cys)
Sources
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.290A>G
- Protein (HGVS p.)
- NP_000240.1:p.(Tyr97Cys)
- GRCh38
- chr3:37001037 A>G
- GRCh37
- chr3:37042528 A>G
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…
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
173 / 1,605,044 alleles
AF 0.000108 · 0 homozygotes · FAF 0.00154
gnomAD v2.1
61 / 251,380 alleles
AF 0.000243 · 0 homozygotes · FAF 0.00153
By genetic ancestry
gnomAD v4.1
AF 0.00011 · 173 / 1,605,044 alleles · 0 hom · FAF 0.0015
| South Asian160 / 90,922 | 0.0018 |
| Middle Eastern1 / 6,060 | 0.00017 |
| Remaining individuals10 / 62,190 | 0.00016 |
| European (non-Finnish)2 / 1,171,952 | 1.7e-06 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00024 · 61 / 251,380 alleles · 0 hom · FAF 0.0015
| South Asian59 / 30,612 | 0.0019 |
| Remaining individuals1 / 6,134 | 0.00016 |
| European (non-Finnish)1 / 113,674 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000107785; MAF= 0.01078%, 173/1605044 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00175975; MAF= 0.17598%, 160/90922 alleles, homozygotes = 0); grpmax FAF= 0.0015372.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000242661; MAF= 0.02427%, 61/251380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00192735; MAF= 0.19273%, 59/30612 alleles, homozygotes = 0); grpmax FAF= 0.00153368.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For MLH1 missense variants, PP3 requires an HCI prior probability of pathogenicity above 0.68. No qualifying HCI prior result was identified, SpliceAI does not support a splice effect with a maximum delta score of 0.01, and the available REVEL and BayesDel scores do not independently satisfy the MLH1 VCEP missense PP3 rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability > 0.68 or non-canonical splice variant with SpliceAI >= 0.2
Evidence considered
- SpliceAI max delta score = 0.01
- REVEL score = 0.603
- BayesDel score = 0.230019
- No HCI prior probability was identified in the retrieved evidence.
Still missing
- An HCI prior probability result would be needed for formal PP3 missense evaluation under the MLH1 VCEP rule.
Sources
BP4 For MLH1 missense variants, BP4 requires an HCI prior probability of pathogenicity below 0.11. No qualifying HCI prior result was identified, and although REVEL is 0.603 and BayesDel is 0.230019, those scores do not substitute for the VCEP missense BP4 rule. Details ▾Hide ▴
Rule
Missense variant with HCI prior probability < 0.11
Evidence considered
- REVEL score = 0.603
- BayesDel score = 0.230019
- No HCI prior probability was identified in the retrieved evidence.
Still missing
- An HCI prior probability result would be needed for formal BP4 evaluation under the MLH1 VCEP rule.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or qualifying intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant at or beyond -21/+7
Evidence considered
- Variant consequence = missense p.(Tyr97Cys)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.603. BayesDel score = 0.230019.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
173 / 1,605,044 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/184486/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37042528-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37001037-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.290A…
- OncoKB ↗www.oncokb.org/gene/MLH1/Y97C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104516914
- 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
This variant is present in gnomAD v4.1 (AF= 0.000107785; MAF= 0.01078%, 173/1605044 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00175975; MAF= 0.17598%, 160/90922 alleles, homozygotes = 0); grpmax FAF= 0.0015372.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000242661; MAF= 0.02427%, 61/251380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00192735; MAF= 0.19273%, 59/30612 alleles, homozygotes = 0); grpmax FAF= 0.00153368.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories) and as likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.603. BayesDel score = 0.230019.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51621158, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.