About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1344G>T, p.(Glu448Asp)
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. 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
The variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.92e-05 (31/1,614,034 alleles, 0 homozygotes), which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability for pathogenicity is 0.0024, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico tools predict a benign effect: BayesDel score is -0.059 (benign range) and SpliceAI predicts no splicing impact (max delta = 0.03). REVEL score of 0.537 is indeterminate and does not override the HCI prior.
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 v2.0 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
31 / 1,614,034 alleles
gnomAD v4.1: 31 / 1,614,034 alleles. Recorded AF 1.92065e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59242e-05; MAF= 0.00159%, 4/251190 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163239; MAF= 0.01632%, 1/6126 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
11 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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 ↗
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
Cancer Hotspots ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 15 not met · 1 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
NM_000249.4:c.1344G>T (p.Glu448Asp) is a missense variant in exon 12 of the MLH1 gene. It is extremely rare in population databases, with an allele frequency of 1.92e-05 in gnomAD v4.1 (31/1,614,034 alleles, 0 homozygotes), meeting PM2 at supporting strength.
Computational evidence strongly predicts a benign effect: the HCI prior probability for pathogenicity is 0.0024 (BP4_Supporting threshold <0.11 met), BayesDel score is -0.059 (benign range), and SpliceAI predicts no splicing impact (max delta = 0.03).
No functional data are available for this variant. It is not included in the VCEP calibrated functional assay documentation, and no publication reports variant-specific functional evidence for c.1344G>T.
No segregation, de novo, or tumor pathology data are available for this variant. The variant has been reported in ClinVar as Uncertain Significance (VariationID 127612, 1-star review status) by 14 clinical laboratories, with one additional submission as Benign and one as Likely Benign.
Applying the InSiGHT VCEP v2.0 combination rules: one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) are met. No criteria at moderate, strong, or very strong strength are met in either direction. This yields a classification of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingThe variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.92e-05 (31/1,614,034 alleles, 0 homozygotes), which is below the VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.92e-05 (31/1
- 614
- 034 alleles
- 0 homozygotes)
- gnomAD v2.1 AF = 1.59e-05 (4/251
- 190 alleles)
- absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0024, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico tools predict a benign effect: BayesDel score is -0.059 (benign range) and SpliceAI predicts no splicing impact (max delta = 0.03). REVEL score of 0.537 is indeterminate and does not override the HCI prior. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0024 (BP4 threshold <0.11 met)
- BayesDel = -0.059
- SpliceAI max delta = 0.03
- REVEL = 0.537 (indeterminate).
Sources
Not met · 15 · evaluated, threshold not reached
PVS1 NM_000249.4:c.1344G>T is a missense variant (p.Glu448Asp) in exon 12 of MLH1. It does not fall into any PVS1-eligible null-variant category under the InSiGHT VCEP v2.0 rules (nonsense/frameshift, canonical ±1,2 splice, large genomic alteration, initiation codon). PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 12 of 19
- not a null variant
- VCEP PVS1 rules do not cover missense substitutions.
Sources
pvs1_variant_assessmentcspec ↗
PS1 No other nucleotide change encoding p.Glu448Asp has been established as Pathogenic by this VCEP. The variant c.1344G>C (also p.E448D) exists but has not been classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. Details ▾Hide ▴
Evidence considered
- VCEP pilot variants spreadsheet contains no entry for codon 448
- no established pathogenic variant at this codon with a different nucleotide change.
Sources
hci_priorcspec ↗
PS2 No de novo occurrence data are available for this variant. VCEP PS2 requires confirmed de novo status with phased parental testing and point-based scoring; no such evidence exists in the case record. Details ▾Hide ▴
Still missing
- No de novo data available. Parental testing would be required to assess PS2.
PS3 No calibrated functional assay data exist for NM_000249.4:c.1344G>T (p.Glu448Asp). The VCEP Functional Assay SVI documentation (MMR assays spreadsheet) does not contain this variant. No publication reports variant-specific functional evidence. The OncoKB entry for E448D is 'Unknown Oncogenic Effect' with no supporting functional data. Details ▾Hide ▴
Evidence considered
- VCEP functional assay documentation does not include c.1344G>T
- no calibrated functional odds for pathogenicity available
- no publications with variant-specific functional data.
Still missing
- Functional assays (in vitro MMR activity assay
- cDNA expression
- or minigene splicing assay) would be required to evaluate PS3.
Sources
PM5 No different missense change at codon 448 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. The VCEP pilot variants spreadsheet contains no MLH1 variant at this codon. Additionally, VCEP PM5 requires PP3 to be supporting for the variant in question, and PP3 is not met (HCI prior = 0.0024). Details ▾Hide ▴
Evidence considered
- No VCEP-classified pathogenic missense comparator at codon 448
- PP3 not supporting (HCI prior 0.0024)
- pm5_candidates.json returned no eligible candidates.
Sources
pm5_candidatescspec ↗
PP1 No co-segregation data are available for this variant. VCEP PP1 requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio; no such evidence exists in the case record. Details ▾Hide ▴
Still missing
- No segregation data available. Family studies would be required to assess PP1.
PP3 The HCI prior probability for pathogenicity is 0.0024, which is far below the VCEP PP3_Supporting threshold of >0.68. SpliceAI predicts no significant splice impact (max delta score = 0.03, below the 0.2 threshold). REVEL score is 0.537 (indeterminate) and BayesDel is -0.059 (benign range), neither of which meets the VCEP PP3 threshold. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0024 (PP3 requires >0.68)
- SpliceAI max delta = 0.03
- REVEL = 0.537
- BayesDel = -0.059.
Sources
PP4 No tumor data (MSI status, immunohistochemistry for MMR proteins) are available for patients carrying this variant. VCEP PP4 requires MSI-H tumors with consistent loss of MMR protein expression; no such evidence exists in the case record. Details ▾Hide ▴
Still missing
- No tumor MSI/IHC data available. Tumor testing would be required to assess PP4.
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 5.798e-05 (0.0058%), which is far below the VCEP BA1 threshold of >=0.001 (0.1%). The variant is not a common polymorphism. Details ▾Hide ▴
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 5.798e-05 (0.0058%), which is below the VCEP BS1 threshold of >=0.0001 to <0.001. The variant is too rare to meet BS1. Details ▾Hide ▴
BS2 No data are available for co-occurrence in trans with a known pathogenic MLH1 variant in a patient with CRC after age 45 without CMMRD features. VCEP BS2 requires phased co-occurrence evidence. Details ▾Hide ▴
Still missing
- No co-occurrence in trans data available. Phase-confirmed co-occurrence studies would be required.
BS3 No functional data demonstrating a benign effect are available for this variant. The VCEP functional assay SVI documentation does not include c.1344G>T. No publication reports variant-specific functional evidence supporting normal MMR function. Details ▾Hide ▴
BS4 No segregation data are available to assess lack of co-segregation with disease. VCEP BS4 requires combined Bayes Likelihood Ratio from pedigrees demonstrating absence of segregation. Details ▾Hide ▴
Still missing
- No segregation data available. Family studies would be required to assess BS4.
BP5 No tumor data are available to demonstrate microsatellite stability (MSS) or intact MMR protein expression in CRC/endometrial tumors from patients carrying this variant. VCEP BP5 requires tumor evidence of MSS and/or preserved MMR protein expression. Details ▾Hide ▴
Still missing
- No tumor MSS/IHC data available. Tumor testing showing MSS with retained MMR expression would be required to assess BP5.
BP7 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000249.4:c.1344G>T is a missense variant (p.Glu448Asp) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous or intronic.
Not assessed · 1 · no assessment recorded
PS5 PS5 is an ACMG criterion for a variant found in a patient with an alternate molecular basis for disease. The InSiGHT VCEP v2.0 does not include PS5 in its criteria specifications, and no alternate molecular basis data are available in the case record. Details ▾Hide ▴
Still missing
- No VCEP specification for PS5
- no alternate molecular basis data available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is marked as Not Applicable for this VCEP according to the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specifications v2.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is marked as Not Applicable for this VCEP according to the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specifications v2.0. The VCEP does not use domain-level evidence for MLH1. Details ▾Hide ▴
Sources
PM3 N/APM3 applies to biallelic variants in trans with a pathogenic variant for recessive disorders (CMMRD context for MLH1). No biallelic data are available and this is not a recessive disorder presentation. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 applies to protein length changes from in-frame deletions/insertions, stop-loss, or initiation codon variants. This is a missense substitution and does not alter protein length. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is marked as Not Applicable for this VCEP according to the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specifications v2.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is marked as Not Applicable for this VCEP. The VCEP notes that the missense variant in a gene with low rate of benign missense changes does not apply for MLH1. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is marked as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is marked as Not Applicable for this VCEP according to the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specifications v2.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is marked as Not Applicable for this VCEP according to the InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specifications v2.0. Details ▾Hide ▴
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is marked as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.1344G>T
- Protein (HGVS p.)
- NP_000240.1:p.(Glu448Asp)
- GRCh38
- chr3:37025942 G>T
- GRCh37
- chr3:37067433 G>T
- ClinVar
- 127612
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
31 / 1,614,034 alleles
AF 1.92e-05 · 0 homozygotes · FAF 5.8e-05
gnomAD v2.1
4 / 251,190 alleles
AF 1.59e-05 · 0 homozygotes · FAF 9.58e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-05 · 31 / 1,614,034 alleles · 0 hom · FAF 5.8e-05
| Middle Eastern2 / 6,084 | 0.00033 |
| Admixed American3 / 59,986 | 5e-05 |
| Remaining individuals2 / 62,486 | 3.2e-05 |
| European (non-Finnish)24 / 1,180,042 | 2e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.6e-05 · 4 / 251,190 alleles · 0 hom · FAF 9.6e-06
| Remaining individuals1 / 6,126 | 0.00016 |
| Admixed American2 / 34,586 | 5.8e-05 |
| European (non-Finnish)1 / 113,602 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.92065e-05; MAF= 0.00192%, 31/1614034 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328731; MAF= 0.03287%, 2/6084 alleles, homozygotes = 0); grpmax FAF= 5.798e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59242e-05; MAF= 0.00159%, 4/251190 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163239; MAF= 0.01632%, 1/6126 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.537
- BayesDel
- -0.059
How the predictions were used
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0024, which is below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico tools predict a benign effect: BayesDel score is -0.059 (benign range) and SpliceAI predicts no splicing impact (max delta = 0.03). REVEL score of 0.537 is indeterminate and does not override the HCI prior. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0024 (BP4 threshold <0.11 met)
- BayesDel = -0.059
- SpliceAI max delta = 0.03
- REVEL = 0.537 (indeterminate).
Sources
PP3 The HCI prior probability for pathogenicity is 0.0024, which is far below the VCEP PP3_Supporting threshold of >0.68. SpliceAI predicts no significant splice impact (max delta score = 0.03, below the 0.2 threshold). REVEL score is 0.537 (indeterminate) and BayesDel is -0.059 (benign range), neither of which meets the VCEP PP3 threshold. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0024 (PP3 requires >0.68)
- SpliceAI max delta = 0.03
- REVEL = 0.537
- BayesDel = -0.059.
Sources
BP7 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000249.4:c.1344G>T is a missense variant (p.Glu448Asp) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous or intronic.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.537. BayesDel score = -0.0591115. HCI prior probability for pathogenicity = 0.0024. Custom PP2 score = 0.002.
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
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PMID 15662714 ↗Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry.Ponti G et al. · 2005Ponti et al. (2005) evaluated microsatellite instability and immunohistochemistry in sebaceous tumors for identification of Muir-Torre syndrome. NM_000249.4:c.1344G>T was not identified or discussed. Only one MSH2 constitutional mutation (2133 C>T) was reported.Does not name this variant
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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.Richards et al. (2015) published the ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a methodological guideline and does not discuss any specific variants.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi et al. (2016) described a standardized DNA variant scoring system for pathogenicity assessments. This is a methodological paper and does not discuss specific MLH1 variants.Does not name this variant
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993GeneReviews entry on Lynch Syndrome (Adam et al.). This is a general clinical reference on Lynch syndrome and does not provide variant-specific data for c.1344G>T.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015Hampel et al. (2015) published an ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. This is a clinical guideline and does not discuss specific MLH1 variants.Does not name this variant
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PMID 25452455 ↗Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.Stoffel EM et al. · 2015Stoffel et al. (2015) published an ASCO clinical practice guideline on hereditary colorectal cancer syndromes. This is a guideline endorsement and does not discuss specific MLH1 variants.Does not name this variant
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PMID 25559809 ↗Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.Chubb D et al. · 2015Chubb et al. (2015) performed exome sequencing of mismatch repair genes in 626 early-onset familial CRC cases. NM_000249.4:c.1344G>T was not identified or discussed in this study.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiPDQ Cancer Genetics Risk Assessment and Counseling summary. This is a general clinical reference and does not provide variant-specific data for c.1344G>T.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp et al. (2017) described Sherloc, a refinement of the ACMG-AMP variant classification criteria. This is a methodological paper and does not discuss specific MLH1 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
31 / 1,614,034 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
11 Uncertain significance · 1 Uncertain Significance · 1 Benign · 1 Likely benign
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/127612/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37067433-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37025942-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37025942-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.1344…
- OncoKB ↗www.oncokb.org/gene/MLH1/E448D
- 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= 1.92065e-05; MAF= 0.00192%, 31/1614034 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328731; MAF= 0.03287%, 2/6084 alleles, homozygotes = 0); grpmax FAF= 5.798e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59242e-05; MAF= 0.00159%, 4/251190 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163239; MAF= 0.01632%, 1/6126 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 127612)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.537. BayesDel score = -0.0591115. HCI prior probability for pathogenicity = 0.0024. Custom PP2 score = 0.002.
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.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.