About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1682A>G, p.(Tyr561Cys)
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 v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Population frequency is below the MLH1 PM2_Supporting threshold. In gnomAD v4.1, the total allele frequency is 3.10936e-06 (5/1608050 alleles) with grpmax filtering allele frequency 8e-07, which is below the threshold of 0.00002 (<1 in 50,000 alleles).
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 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: 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
5 / 1,608,050 alleles
gnomAD v4.1: 5 / 1,608,050 alleles. Recorded AF 3.10936e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 · 3 not met · 13 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.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.
This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 3.10936e-06 and grpmax filtering allele frequency 8e-07, which is below the MLH1 PM2_Supporting threshold of 0.00002.
No variant-specific calibrated functional assay result for this variant was identified in the reviewed MMR functional assay materials, so functional evidence was not used to support or refute pathogenicity.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and available in silico evidence was insufficient to assign the MLH1 missense PP3 or BP4 rules without an HCI-prior value.
No criteria match.
Met · 1
PM2 SupportingPopulation frequency is below the MLH1 PM2_Supporting threshold. In gnomAD v4.1, the total allele frequency is 3.10936e-06 (5/1608050 alleles) with grpmax filtering allele frequency 8e-07, which is below the threshold of 0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 total AF=3.10936e-06 (5/1608050)
- gnomAD v4.1 grpmax FAF=8e-07
- gnomAD v2.1 total AF=3.18512e-05 (1/31396)
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.Tyr561Cys, and does not fall into the MLH1 PVS1 null-variant categories. The variant-level PVS1 assessment states that it is not a nonsense, frameshift, or canonical ±1/2 splice variant, so PVS1 is not applied. Details ▾Hide ▴
Rule
PVS1 is reserved for MLH1 null-variant mechanisms such as qualifying nonsense, frameshift, canonical splice, exon-level loss, qualifying RNA-proven splice defects, or initiation codon variants.
Evidence considered
- MLH1 is eligible for PVS1 in general
- Variant bucket=other
- Canonical splice consensus=false
Sources
BA1 Population frequency does not meet the MLH1 BA1 threshold. In gnomAD v4.1, the highest filtering allele frequency is 8e-07, which is below the BA1 threshold of 0.001 (0.1%). Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF=8e-07
Sources
BS1 Population frequency does not meet the MLH1 BS1 threshold. In gnomAD v4.1, the highest filtering allele frequency is 8e-07, which is below the BS1 range of 0.0001 to less than 0.001. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF=8e-07
Sources
Not assessed · 13 · no assessment recorded
PS1 No previously established MLH1 pathogenic or likely pathogenic variant encoding the same amino acid change by a different nucleotide change was identified in the reviewed VCEP materials, so PS1 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed VCEP pilot variant spreadsheet
- no qualifying same-amino-acid comparator identified for p.Tyr561Cys
Still missing
- No qualifying same-amino-acid VCEP comparator was identified in the reviewed materials.
Sources
cspec ↗vcep_v_c_e_p___p_i_l_o_t___v_a_r_i_a_n_t_s_______m_m_r
PS2 No confirmed de novo occurrence of this variant in an individual with an MLH1-consistent mismatch repair-deficient tumor was identified. Details ▾Hide ▴
Evidence considered
- No qualifying PS2 de novo evidence identified
Still missing
- Parental confirmation and qualifying tumor data were not available.
Sources
PS3 No variant-specific calibrated functional assay result demonstrating damaging MLH1 function was identified, so PS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- Reviewed MMR functional assay documentation and flowchart
- no qualifying pathogenic result identified for p.Tyr561Cys
Still missing
- No variant-specific pathogenic functional assay result was identified in the reviewed functional materials.
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
PM3 No confirmed in trans observation with another pathogenic or likely pathogenic MLH1 variant in a patient meeting constitutional mismatch repair deficiency criteria was identified. Details ▾Hide ▴
Evidence considered
- No qualifying PM3 case evidence identified
Still missing
- Phase-confirmed trans data and CMMRD phenotype scoring were not available.
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PM5 No previously established pathogenic or likely pathogenic missense comparator at MLH1 codon 561 was identified in the reviewed VCEP materials, and PP3 was not assigned; therefore PM5 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed VCEP pilot variant spreadsheet
- no qualifying same-residue comparator identified for Tyr561
Still missing
- No qualifying same-residue VCEP comparator was identified in the reviewed materials.
Sources
cspec ↗vcep_v_c_e_p___p_i_l_o_t___v_a_r_i_a_n_t_s_______m_m_r
PP1 No segregation data showing co-segregation of this variant with Lynch syndrome-associated disease in affected relatives were identified. Details ▾Hide ▴
Evidence considered
- No qualifying PP1 segregation evidence identified
Still missing
- Family study data and Bayes likelihood ratio calculations were not available.
Sources
PP3 SpliceAI does not support a splice defect for this variant, with a maximum delta score of 0.01, and the MLH1 PP3 missense rule requires an HCI-prior probability above 0.68 or 0.81, which was not available. Available in silico evidence is therefore insufficient to apply PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score=0.01
- No HCI-prior value available
Still missing
- HCI-prior probability for this missense change was not available.
Sources
PP4 No tumor microsatellite instability, immunohistochemistry, or MLH1 promoter methylation data were identified to support an MLH1-consistent mismatch repair-deficient phenotype. Details ▾Hide ▴
Evidence considered
- No qualifying PP4 tumor evidence identified
Still missing
- Tumor MSI/IHC and MLH1 promoter methylation results were not available.
Sources
BS2 No confirmed observation of this variant in trans with a known pathogenic MLH1 variant in an individual without clinical evidence of constitutional mismatch repair deficiency was identified. Details ▾Hide ▴
Evidence considered
- No qualifying BS2 case evidence identified
Still missing
- Phase-confirmed co-occurrence data and phenotype details were not available.
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
BS3 No variant-specific calibrated functional evidence showing proficient MLH1 function was identified, so BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- Reviewed MMR functional assay documentation and flowchart
- no qualifying benign result identified for p.Tyr561Cys
Still missing
- No variant-specific benign functional assay result was identified in the reviewed functional materials.
Sources
cspec ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
BS4 No family segregation study showing lack of co-segregation with Lynch syndrome-associated disease was identified. Details ▾Hide ▴
Evidence considered
- No qualifying BS4 segregation evidence identified
Still missing
- Segregation data and Bayes likelihood ratio calculations were not available.
Sources
BP4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the non-canonical splice threshold of 0.1; however, this is a missense variant, and the MLH1 BP4 missense rule requires an HCI-prior probability below 0.11, which was not available. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score=0.01
- No HCI-prior value available
Still missing
- HCI-prior probability for this missense change was not available.
Sources
BP5 No tumor data showing mismatch repair findings inconsistent with MLH1-associated disease, and no qualifying MLH1 methylation or BRAF V600E evidence, were identified. Details ▾Hide ▴
Evidence considered
- No qualifying BP5 tumor evidence identified
Still missing
- Tumor MSI/IHC and methylation data were not available.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 N/APS4 is not applicable for this VCEP framework because proband counting is not used for MMR variant classification when tumor immunohistochemistry data are available for PP4. Details ▾Hide ▴
PM1 N/APM1 is not applicable for this VCEP framework because recognized mutational hot spots are not used for MMR variant classification. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
- Cancer Hotspots did not identify a statistically significant hotspot
Sources
PM4 N/APM4 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
PM6 N/APM6 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
PP2 N/APP2 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
PP5 N/APP5 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
BP1 N/ABP1 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
BP2 N/ABP2 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
BP3 N/ABP3 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
BP6 N/ABP6 is not applicable for this VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion designated not applicable by the MLH1 VCEP specification
Sources
BP7 N/ABP7 is a silent or intronic variant rule and does not apply to this missense variant. Details ▾Hide ▴
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.1682A>G
- Protein (HGVS p.)
- NP_000240.1:p.(Tyr561Cys)
- GRCh38
- chr3:37042282 A>G
- GRCh37
- chr3:37083773 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
5 / 1,608,050 alleles
AF 3.11e-06 · 0 homozygotes · FAF 8e-07
gnomAD v2.1
1 / 31,396 alleles
AF 3.19e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,608,050 alleles · 0 hom · FAF 8e-07
| African/African American1 / 74,794 | 1.3e-05 |
| European (non-Finnish)4 / 1,174,522 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,396 alleles · 0 hom
| African/African American1 / 8,712 | 0.00011 |
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= 3.10936e-06; MAF= 0.00031%, 5/1608050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33701e-05; MAF= 0.00134%, 1/74794 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI does not support a splice defect for this variant, with a maximum delta score of 0.01, and the MLH1 PP3 missense rule requires an HCI-prior probability above 0.68 or 0.81, which was not available. Available in silico evidence is therefore insufficient to apply PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score=0.01
- No HCI-prior value available
Still missing
- HCI-prior probability for this missense change was not available.
Sources
BP4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the non-canonical splice threshold of 0.1; however, this is a missense variant, and the MLH1 BP4 missense rule requires an HCI-prior probability below 0.11, which was not available. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score=0.01
- No HCI-prior value available
Still missing
- HCI-prior probability for this missense change was not available.
Sources
BP7 N/ABP7 is a silent or intronic variant rule and does not apply to this missense variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
5 / 1,608,050 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/483536/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37083773-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37042282-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.1682…
- OncoKB ↗www.oncokb.org/gene/MLH1/Y561C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.1682A%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
This variant is present in gnomAD v4.1 (AF= 3.10936e-06; MAF= 0.00031%, 5/1608050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33701e-05; MAF= 0.00134%, 1/74794 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.