About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1637A>G, p.(Lys546Arg)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Extremely rare in gnomAD v4.1: grpmax filtering allele frequency = 1.24e-06, which is below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Observed in 6/1,613,836 alleles (0 heterozygotes), with highest subpopulation frequency in African/African American (AF = 1.34e-05). Absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
HCI prior probability for pathogenicity = 0.0023, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors support a benign effect: REVEL = 0.469 (not predictive of pathogenicity), BayesDel = -0.0407 (slightly benign-leaning).
Recorded classification: Not classified
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 Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; maps to Uncertain Significance - Conflicting Evidence.
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
6 / 1,613,836 alleles
gnomAD v4.1: 6 / 1,613,836 alleles. Recorded AF 3.71785e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75982e-05; MAF= 0.00176%, 2/113648 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.360 maximum delta
Recorded SpliceAI maximum delta score: 0.360. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
12 reported laboratory submissions
9 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign.
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
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 v2.0.0, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
HCI prior probability for pathogenicity is 0.0023, meeting BP4_Supporting per InSiGHT VCEP v2.0.0 (threshold <0.11). REVEL (0.469) and BayesDel (-0.0407) are consistent with a benign in silico profile.
Extremely rare in gnomAD v4.1 (grpmax FAF = 1.24e-06; 6/1,613,836 alleles, 0 homozygotes), meeting PM2_Supporting per InSiGHT VCEP v2.0.0 (threshold <0.00002). Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar (Variation ID: 127617) with submissions of Uncertain Significance (10 clinical laboratories), Benign (1), and Likely Benign (1); no expert panel classification is available.
NM_000249.4:c.1637A>G (p.Lys546Arg) was observed in 1 of 711 patients with hereditary breast cancer in a Russian case-control study (PMID:32547938); no variant-specific MSI, IHC, or functional data were reported.
No criteria match.
Met · 2
PM2 SupportingExtremely rare in gnomAD v4.1: grpmax filtering allele frequency = 1.24e-06, which is below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Observed in 6/1,613,836 alleles (0 heterozygotes), with highest subpopulation frequency in African/African American (AF = 1.34e-05). Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
BP4 SupportingHCI prior probability for pathogenicity = 0.0023, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors support a benign effect: REVEL = 0.469 (not predictive of pathogenicity), BayesDel = -0.0407 (slightly benign-leaning). Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0023 (<0.11 threshold)
- REVEL score = 0.469
- BayesDel score = -0.0407
Sources
hci_priorrevelbayesdel
Not met · 13 · evaluated, threshold not reached
PS1 No different underlying nucleotide change encoding the same amino acid substitution (Lys546Arg) has been established as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. Details ▾Hide ▴
No further detail was recorded.
PS2 No de novo observation reported in any reviewed literature. No publication identified a proband with confirmed maternity and paternity and a MMR-deficient LS-spectrum tumor carrying this variant. Details ▾Hide ▴
No further detail was recorded.
PS3 This variant is not listed in the VCEP calibrated functional assay documentation (Functional-assay-SVI-documentation-MMR.xlsx) and no variant-specific functional data demonstrating a damaging effect on MMR function were identified in any reviewed publication. Details ▾Hide ▴
Still missing
- No functional assay data available for NM_000249.4:c.1637A>G (p.Lys546Arg) in calibrated or non-calibrated assays
PM5 No different missense variant at amino acid residue Lys546 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. Additionally, PM5 requires PP3 to be supporting, which is not met (HCI prior = 0.0023). Details ▾Hide ▴
No further detail was recorded.
PP1 No co-segregation data available for this variant in any reviewed publication. No pedigree analysis with Bayes Likelihood Ratio could be performed. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 HCI prior probability for pathogenicity = 0.0023, well below the VCEP PP3_Supporting threshold of >0.68. The SpliceAI-based PP3 rule (delta ≥0.2) applies only to non-canonical splice site variants and does not apply to this exonic missense variant. REVEL score = 0.469 and BayesDel score = -0.0407 are not informative in either direction. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0023
Sources
hci_prior
PP4 No MSI-H tumor data or MMR protein IHC loss data reported for this specific variant in any reviewed publication. The variant was observed in a breast cancer case-control study (PMID:32547938) but individual variant-level MSI/IHC results were not reported. Details ▾Hide ▴
Still missing
- No tumor MSI/IHC data available for this variant
BA1 gnomAD v4 grpmax filtering allele frequency = 1.24e-06, far below the VCEP BA1 threshold of ≥0.001 (0.1%). Details ▾Hide ▴
BS1 gnomAD v4 grpmax filtering allele frequency = 1.24e-06, below the VCEP BS1 threshold of ≥0.0001 (0.01%). Details ▾Hide ▴
BS2 No evidence of co-occurrence in trans with a known pathogenic MLH1 variant in a patient meeting the specified clinical criteria (CRC after age 45 or other LS cancer above median onset age, without CMMRD features). Details ▾Hide ▴
No further detail was recorded.
BS3 This variant is not listed in the VCEP calibrated functional assay documentation and no variant-specific functional data demonstrating proficient MMR function were identified in any reviewed publication. Details ▾Hide ▴
Still missing
- No functional assay data available
BS4 No co-segregation analysis data available for this variant. No pedigree data demonstrating lack of segregation with disease could be assessed. Details ▾Hide ▴
Still missing
- No segregation data available
BP5 No tumor data demonstrating MSS status, lack of MMR protein loss, BRAF V600E mutation, or MLH1 promoter methylation were reported for this variant in any reviewed publication. Details ▾Hide ▴
Still missing
- No tumor phenotype data available
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant p.Lys546Arg; not a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon-level deletion). Does not meet any PVS1 rule under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPVCEP rules: PS4 is not utilized for MMR variant classification using proband counting, due to the availability of tumor IHC data for variant classification via PP4. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPVCEP rules: there are no recognized mutational hot spots in MMR genes that can be used for classification purposes. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPVCEP rules: PM6 (assumed de novo without confirmation of maternity and paternity) is superseded by PS2 in this framework and is explicitly marked Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPVCEP rules: PP2 (missense variant in a gene with low rate of benign missense changes) does not apply for MLH1. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPVCEP rules: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPVCEP rules: BP1 (missense variant in a gene where only loss of function causes disease) does not apply for MLH1. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPVCEP rules: BP2 is not used; BS2 is used instead for trans co-occurrence assessment. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPIn-frame deletions/insertions in repetitive regions not applicable for a missense substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPVCEP rules: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7; this is a missense substitution variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not defined or used by the InSiGHT MLH1 VCEP (version 2.0.0). This criterion does not appear in the CSPEC criteria set for this gene. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.1637A>G
- Protein (HGVS p.)
- NP_000240.1:p.(Lys546Arg)
- GRCh38
- chr3:37040264 A>G
- GRCh37
- chr3:37081755 A>G
- ClinVar
- 127617
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
6 / 1,613,836 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
2 / 251,318 alleles
AF 7.96e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,613,836 alleles · 0 hom · FAF 1.2e-06
| African/African American1 / 74,890 | 1.3e-05 |
| European (non-Finnish)5 / 1,179,892 | 4.2e-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 8e-06 · 2 / 251,318 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)2 / 113,648 | 1.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71785e-06; MAF= 0.00037%, 6/1613836 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33529e-05; MAF= 0.00134%, 1/74890 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75982e-05; MAF= 0.00176%, 2/113648 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.469
- BayesDel
- -0.041
How the predictions were used
BP4 SupportingHCI prior probability for pathogenicity = 0.0023, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors support a benign effect: REVEL = 0.469 (not predictive of pathogenicity), BayesDel = -0.0407 (slightly benign-leaning). Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0023 (<0.11 threshold)
- REVEL score = 0.469
- BayesDel score = -0.0407
Sources
hci_priorrevelbayesdel
PP3 HCI prior probability for pathogenicity = 0.0023, well below the VCEP PP3_Supporting threshold of >0.68. The SpliceAI-based PP3 rule (delta ≥0.2) applies only to non-canonical splice site variants and does not apply to this exonic missense variant. REVEL score = 0.469 and BayesDel score = -0.0407 are not informative in either direction. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0023
Sources
hci_prior
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7; this is a missense substitution variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.36). REVEL score = 0.469. BayesDel score = -0.0406917. HCI prior probability for pathogenicity = 0.0023. MAPP score = 3.83. Custom PP2 score = 0.016.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 25070057 ↗Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.No paper-specific finding is recorded.
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PMID 25741868 ↗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.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a general methodological paper describing the framework for variant classification. NM_000249.4:c.1637A>G was not identified in this paper.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a standardized DNA variant scoring system (Sherloc precursor) for pathogenicity assessments in Mendelian disorders. NM_000249.4:c.1637A>G was not identified in this paper.Does not name this variant
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PMID 32547938 ↗Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.Nikitin AG et al. · 2020c.1637A>G in MLH1 was identified in 1 of 711 patients with hereditary breast cancer in a case-control study from the Volga and Central Federal Districts of the Russian Federation. The variant was listed among 10 MLH1 mutations detected but was not among those highlighted as significantly associated with hereditary breast cancer; it was classified as a variant of uncertain significance. No variant-specific MSI, IHC, or functional data were reported.Names this variant
Quoted passage
we performed Targeted NGS and, in a cohort comprising 711 participants with hereditary BC, identified in 17 participants 10 mutations in MLH1 gene (c.945C>G, c.1637A>G, c.803A>G, c.1321G>A, c.1937A>G, c.-7C>T, c.2194A>G, c.472A>G, c.2194A>G, andc.1090A>C)
Results and Discussion, paragraph 6
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PMID 32832836 ↗Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.Matejcic M et al. · 2020Investigated pathogenic variants in cancer predisposition genes and prostate cancer risk in men of African ancestry. NM_000249.4:c.1637A>G was not identified in this paper.Does not name this variant
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PMID 23408351 ↗Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.Revised guidelines for the clinical management of Lynch syndrome by a group of European experts (Mallorca group). NM_000249.4:c.1637A>G was not identified in this paper.Does not name this variant
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PMID 23535968 ↗Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.No paper-specific finding is recorded.
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PMID 24310308 ↗ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, FAP, and MAP). NM_000249.4:c.1637A>G was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,613,836 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.360
Open source ↗
ClinVar
9 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1564688410
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/127617/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37081755-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37040264-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37040264-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.1637…
- OncoKB ↗www.oncokb.org/gene/MLH1/K546R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.1637A%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= 3.71785e-06; MAF= 0.00037%, 6/1613836 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33529e-05; MAF= 0.00134%, 1/74890 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.75982e-05; MAF= 0.00176%, 2/113648 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 127617)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.36). REVEL score = 0.469. BayesDel score = -0.0406917. HCI prior probability for pathogenicity = 0.0023. MAPP score = 3.83. Custom PP2 score = 0.016.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.