About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1655C>T, p.(Thr552Ile)
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
This variant is extremely rare in population databases. In gnomAD v4.1, it is observed in 2 of 1,612,688 alleles (grpmax filtering AF = 3.65e-06), meeting the InSiGHT VCEP threshold for PM2_Supporting (AF < 0.00002, i.e., <1 in 50,000 alleles). It is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability for pathogenicity is 0.0197, which meets the InSiGHT VCEP BP4_Supporting threshold for missense variants (HCI prior <0.11). SpliceAI predicts no splicing impact (max delta = 0.01). Multiple in silico predictors (REVEL 0.268, BayesDel 0.361) are consistent with a variant of uncertain significance and do not suggest a damaging effect.
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
2 / 1,612,688 alleles
gnomAD v4.1: 2 / 1,612,688 alleles. Recorded AF 1.24017e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
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.
29 criteria with recorded statuses: 2 met · 5 not met · 8 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.1655C>T (p.Thr552Ile) is a missense variant in exon 14 of MLH1 that is extremely rare in population databases, observed in 2 of 1,612,688 alleles in gnomAD v4.1 (grpmax filtering AF = 3.65e-06), meeting PM2_Supporting under the InSiGHT MLH1 VCEP v2.0.0.
In silico predictors support a benign computational profile: the MLH1-specific HCI prior probability for pathogenicity is 0.0197, meeting BP4_Supporting (threshold <0.11). SpliceAI predicts no splicing impact (max delta = 0.01). REVEL (0.268) and BayesDel (0.361) are in the indeterminate range.
This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 1467499) with no expert panel classification. No publications were identified that specifically report this variant.
No functional data, segregation data, tumor phenotype data, or de novo observations are available for this variant. Multiple criteria (PS3, PP1, PP4, PS2, BS3, BS4, BS2, BP5) could not be assessed due to absence of evidence.
Under the InSiGHT MLH1 VCEP v2.0.0 combining rules, one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) with no other criteria met results in classification as Uncertain Significance — conflicting or insufficient evidence to classify.
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v4.1, it is observed in 2 of 1,612,688 alleles (grpmax filtering AF = 3.65e-06), meeting the InSiGHT VCEP threshold for PM2_Supporting (AF < 0.00002, i.e., <1 in 50,000 alleles). It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2/1
- 612
- 688 alleles
- grpmax FAF = 3.65e-06.
- gnomAD v2.1: absent.
- gnomAD-Canada v1.0: absent.
- Meets VCEP PM2_Supporting threshold of <0.00002.
Sources
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0197, which meets the InSiGHT VCEP BP4_Supporting threshold for missense variants (HCI prior <0.11). SpliceAI predicts no splicing impact (max delta = 0.01). Multiple in silico predictors (REVEL 0.268, BayesDel 0.361) are consistent with a variant of uncertain significance and do not suggest a damaging effect. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0197
- meets BP4_Supporting threshold (<0.11).
- SpliceAI max delta: 0.01 (no predicted splicing impact).
- REVEL: 0.268
- BayesDel: 0.361 (indeterminate
- not predictive of pathogenicity).
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No other nucleotide change encoding the same amino acid substitution (Thr552Ile) has been classified as Pathogenic by the InSiGHT VCEP. The VCEP pilot variant spreadsheet does not include any codon 552 variant, and no VCEP-classified comparator exists. Details ▾Hide ▴
Evidence considered
- HCI-PRIORS lists three codon 552 missenses (c.1655C>A/p.T552N
- c.1655C>G/p.T552S
- c.1655C>T/p.T552I)
- none are present in the VCEP pilot variant spreadsheet as Pathogenic.
- No same-amino-acid comparator classified as Pathogenic by this VCEP.
Sources
hci_priorvcep_vcep_pilot_variants_mmr
PM5 This is a missense change at residue 552 (p.Thr552Ile). However, no different missense change at the same residue has been classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP. The two other codon 552 missense variants (c.1655C>A/p.T552N and c.1655C>G/p.T552S) are not present in the VCEP pilot variant spreadsheet, and no VCEP-classified comparator exists. Details ▾Hide ▴
Evidence considered
- Other codon 552 missenses (T552N
- T552S) exist but are not VCEP-classified as Pathogenic or Likely Pathogenic.
- No qualifying PM5 comparator at residue 552.
Sources
hci_priorvcep_vcep_pilot_variants_mmrpm5_candidates
PP3 The HCI prior probability for pathogenicity is 0.0197, which does not meet the VCEP thresholds for PP3 (Moderate: >0.81; Supporting: >0.68 and ≤0.81). SpliceAI predicts no splicing impact (max delta = 0.01), below the 0.2 threshold for predicted splice defects. REVEL (0.268) and BayesDel (0.361) are in the indeterminate range and do not independently establish PP3 under VCEP rules. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0197 (below PP3_Supporting threshold of >0.68).
- SpliceAI max delta: 0.01 (below 0.2 threshold for splice prediction).
- REVEL: 0.268
- BayesDel: 0.361 (indeterminate
- not used by VCEP for PP3).
Sources
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), far below the InSiGHT VCEP BA1 threshold of ≥0.001 (≥0.1%). BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 3.65e-06
- well below BA1 threshold of ≥0.001.
Sources
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), below the InSiGHT VCEP BS1 threshold of ≥0.0001 (≥0.01%). BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 3.65e-06
- below BS1 threshold of ≥0.0001.
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observations have been reported for this variant. No publications or ClinVar submissions document a confirmed de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar submissions
- literature
- or VCEP materials.
Still missing
- De novo occurrence data would be required to assess PS2.
PS3 No variant-specific functional data are available. The variant was not found in the VCEP Functional-assay-SVI-documentation-MMR spreadsheet. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications report functional assay data for c.1655C>T. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- VCEP functional assay documentation: no match for c.1655C>T.
- No publications with functional data for this variant.
Still missing
- Functional assay data (e.g.
- MMR activity assay
- protein expression
- splicing assay) would be required to assess PS3.
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for this variant. No publications or ClinVar submissions report segregation analysis in affected families. Details ▾Hide ▴
Evidence considered
- No segregation data in any reviewed source.
Still missing
- Co-segregation data in affected pedigrees would be required to assess PP1.
PP4 No tumor IHC or MSI data are available for this variant. No publications or ClinVar submissions report MSI-H status or MMR protein expression in tumors from carriers of this variant. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available for this variant.
Still missing
- Tumor MSI/IHC data from carriers would be required to assess PP4.
BS2 No data on co-occurrence in trans with a known pathogenic MLH1 variant are available. Assessment of BS2 would require confirmed phase testing in an individual with colorectal cancer after age 45 without CMMRD features. Details ▾Hide ▴
Evidence considered
- No co-occurrence data available.
Still missing
- Co-occurrence in trans with a known pathogenic variant would be required to assess BS2.
BS3 No variant-specific functional data demonstrating a benign effect are available. The variant was not found in the VCEP functional assay documentation, and no publications report functional evidence of normal MMR activity for c.1655C>T. Details ▾Hide ▴
Evidence considered
- VCEP functional assay documentation: no match.
- No publications with benign functional data for this variant.
Still missing
- Functional assay data demonstrating normal MMR function would be required to assess BS3.
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data are available to assess lack of segregation with disease. No publications or ClinVar submissions report segregation analysis for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Lack of co-segregation data in pedigrees would be required to assess BS4.
BP5 No data on tumors with MSS or normal MMR protein expression in carriers of this variant are available. No BRAF V600E or MLH1 methylation data have been reported in association with this variant. Details ▾Hide ▴
Evidence considered
- No tumor MSS/IHC data or methylation/BRAF data available.
Still missing
- Tumor data (MSS
- normal IHC
- BRAF/methylation) from carriers would be required to assess BP5.
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense substitutions under the InSiGHT MLH1 VCEP v2.0.0 framework. The VCEP reserves PVS1 for null variants (nonsense, frameshift, canonical splice ±1,2, initiation codon, or confirmed splicing aberrations). NM_000249.3:c.1655C>T is a missense change (p.Thr552Ile) and does not fall into any PVS1 bucket. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 552 in exon 14
- variant bucket 'other' per PVS1 decision tree
- VCEP PVS1 criteria do not cover missense variants.
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPPS4 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. 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 classification.
Sources
PM1 VCEPPM1 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. 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 ▴
Evidence considered
- VCEP explicitly marks PM1 as Not Applicable for MLH1 classification.
Sources
PM3 N/ASkipped by user directive. PM3 requires trans observation with a known pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 applies to protein-length-changing variants (in-frame deletions/insertions, stop-loss); not applicable to a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. The VCEP directs users to PS2 instead for de novo assessment. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No expert panel has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks PP5 as Not Applicable.
- No expert panel classification exists for this variant.
Sources
BP1 VCEPBP1 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
BP3 VCEPBP3 applies only to in-frame insertions/deletions in repetitive regions; not applicable to a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not applicable under the InSiGHT MLH1 VCEP v2.0.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000249.3:c.1655C>T is a missense substitution (p.Thr552Ile) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT MLH1 VCEP v2.0.0 criteria set. This criterion does not exist in the current framework. Details ▾Hide ▴
Evidence considered
- PS5 is absent from the InSiGHT MLH1 VCEP v2.0.0 criteria definitions.
Sources
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.3
- Coding (HGVS c.)
- NM_000249.3:c.1655C>T
- Protein (HGVS p.)
- NP_000240.1:p.(Thr552Ile)
- GRCh38
- chr3:37040282 C>T
- GRCh37
- chr3:37081773 C>T
- ClinVar
- 1467499
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in MLH1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,612,688 alleles
AF 1.24e-06 · 0 homozygotes · FAF 3.65e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,612,688 alleles · 0 hom · FAF 3.7e-06
| South Asian2 / 91,052 | 2.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24017e-06; MAF= 0.00012%, 2/1612688 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19655e-05; MAF= 0.00220%, 2/91052 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.268
- BayesDel
- 0.361
How the predictions were used
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0197, which meets the InSiGHT VCEP BP4_Supporting threshold for missense variants (HCI prior <0.11). SpliceAI predicts no splicing impact (max delta = 0.01). Multiple in silico predictors (REVEL 0.268, BayesDel 0.361) are consistent with a variant of uncertain significance and do not suggest a damaging effect. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0197
- meets BP4_Supporting threshold (<0.11).
- SpliceAI max delta: 0.01 (no predicted splicing impact).
- REVEL: 0.268
- BayesDel: 0.361 (indeterminate
- not predictive of pathogenicity).
Sources
PP3 The HCI prior probability for pathogenicity is 0.0197, which does not meet the VCEP thresholds for PP3 (Moderate: >0.81; Supporting: >0.68 and ≤0.81). SpliceAI predicts no splicing impact (max delta = 0.01), below the 0.2 threshold for predicted splice defects. REVEL (0.268) and BayesDel (0.361) are in the indeterminate range and do not independently establish PP3 under VCEP rules. Details ▾Hide ▴
Evidence considered
- HCI prior: 0.0197 (below PP3_Supporting threshold of >0.68).
- SpliceAI max delta: 0.01 (below 0.2 threshold for splice prediction).
- REVEL: 0.268
- BayesDel: 0.361 (indeterminate
- not used by VCEP for PP3).
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000249.3:c.1655C>T is a missense substitution (p.Thr552Ile) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.268. BayesDel score = 0.361201. HCI prior probability for pathogenicity = 0.0197. MAPP score = 4.37. Custom PP2 score = 0.457.
6 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
-
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 S et al. · 2015This is the ACMG/AMP standards and guidelines for sequence variant interpretation. It provides the general framework for variant classification but does not discuss MLH1 c.1655C>T or any specific variant at the codon 552 residue.Does not name this variant
-
PMID 11598466 ↗Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.Church J et al. · 2001Practice parameters for identification and testing of patients at risk for dominantly inherited colorectal cancer. No abstract available; no variant-specific content expected from this guideline document.Does not name this variant
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004Cancer genetic risk assessment and counseling recommendations from NSGC. The abstract discusses general genetic counseling practice but does not mention MLH1 c.1655C>T or any specific variant.Does not name this variant
-
PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993Lynch Syndrome GeneReview. No abstract available; expected to provide general gene-level review of Lynch syndrome rather than variant-specific data.Does not name this variant
-
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.Weissman SM et al. · 2012This is a joint practice guideline from NSGC and CGA-ICC on identifying individuals at risk for Lynch syndrome. It discusses general testing algorithms for Lynch syndrome but does not mention MLH1 c.1655C>T or any specific MLH1 variant at codon 552.Does not name this variant
-
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. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. The abstract discusses general referral indications but does not mention MLH1 c.1655C>T or any specific variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,612,688 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
3 Uncertain significance
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/1467499/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37081773-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37040282-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37040282-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.3%3Ac.1655…
- OncoKB ↗www.oncokb.org/gene/MLH1/T552I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.1655C%3ET
- 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= 1.24017e-06; MAF= 0.00012%, 2/1612688 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19655e-05; MAF= 0.00220%, 2/91052 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
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 Uncertain significance (3 clinical laboratories). (ClinVarID = 1467499)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.268. BayesDel score = 0.361201. HCI prior probability for pathogenicity = 0.0197. MAPP score = 4.37. Custom PP2 score = 0.457.
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.