About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.630G>A, p.(Met210Ile)
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 MSH2 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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability of pathogenicity for c.630G>A (p.M210I) is 0.0035, which is below the VCEP BP4_supporting threshold of <0.11. This indicates that computational evidence predicts no damaging effect on the gene product, supporting a benign interpretation.
Recorded classification: Uncertain significance
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP4 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
10 / 1,613,900 alleles
gnomAD v4.1: 10 / 1,613,900 alleles. Recorded AF 6.19617e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.97951e-06; MAF= 0.00080%, 2/250642 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53253e-05; MAF= 0.00653%, 2/30616 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
1 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113236220, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 6 not met · 8 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_000251.3:c.630G>A (p.Met210Ile) is a rare missense variant in MSH2 exon 3 observed at extremely low frequency in gnomAD v4.1 (AF = 6.20e-06; 10/1,613,900 alleles; grpmax FAF = 4.37e-05). The grpmax filtering AF exceeds the VCEP PM2_supporting threshold of <2e-05, so PM2 is not met.
Computational evidence supports a benign interpretation: the HCI prior probability of pathogenicity is 0.0035, meeting the VCEP BP4_supporting threshold of <0.11. SpliceAI predicts no splicing impact (max delta = 0.04). REVEL score is 0.4 and BayesDel score is -0.059, both consistent with a neutral prediction.
No functional data specific to p.M210I were retrievable from the calibrated deep mutational scan by Jia et al. (2021, PMID 33357406), though this assay is recognized by the VCEP SVI documentation. PS3 and BS3 remain not assessed pending retrieval of the variant-specific LOF score from the study's supplementary data.
This variant has been reported in ClinVar as Likely benign by Ambry Genetics and Benign by Invitae (ClinVar ID 577710, review status: criteria provided, single submitter, 1-star). However, PP5 and BP6 are explicitly not applicable under the InSiGHT MMR VCEP v2.0, and the review status does not meet 3-star expert panel criteria.
No tumor pathology, segregation, de novo, or case-control data were available for this variant. Criteria dependent on clinical or family-level evidence (PS2, PP1, PP4, BS2, BS4, BP5) could not be assessed.
Under the InSiGHT MMR VCEP v2.0 combining rules, the single BP4_supporting criterion does not meet the threshold for Likely Benign (≥2 supporting benign criteria required per Rule 19) or Benign classification. The variant is classified as a Variant of Uncertain Significance.
No criteria match.
Met · 1
BP4 SupportingThe HCI prior probability of pathogenicity for c.630G>A (p.M210I) is 0.0035, which is below the VCEP BP4_supporting threshold of <0.11. This indicates that computational evidence predicts no damaging effect on the gene product, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0035
- well below the VCEP BP4_supporting threshold of <0.11. SpliceAI max delta = 0.04 (<0.1) confirms no predicted splicing impact.
Sources
hci_priorcspec ↗
Not met · 6 · evaluated, threshold not reached
PS1 c.630G>A encodes p.Met210Ile. No alternate nucleotide change at codon 630 producing the same amino acid change (Met210Ile) has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP. No evidence of any other nucleotide substitution resulting in M210I with a prior P/LP classification was identified in ClinVar or VCEP pilot variant records. Details ▾Hide ▴
Evidence considered
- No same-amino-acid comparator with a different nucleotide change classified as P/LP by the VCEP was identified.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
PM2 The VCEP PM2_supporting threshold requires gnomAD v4 grpmax filtering allele frequency < 0.00002 (<1 in 50,000 alleles). The observed gnomAD v4.1 grpmax FAF for this variant is 4.369e-05 (4.37 × 10⁻⁵), which exceeds the threshold. Although the variant is very rare (total AF = 6.20e-06; 10/1,613,900 alleles), the grpmax filtering AF does not meet the VCEP-defined cutoff. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 4.369e-05 exceeds the VCEP PM2 threshold of <2e-05.
Sources
PM5 VCEP PM5 requires a different missense change at the same amino acid residue (Met210) classified as Pathogenic or Likely Pathogenic by the InSiGHT VCEP at the protein level. No such comparator was identified. The pm5_candidates search returned no same-residue candidates. Furthermore, VCEP PM5 requires PP3 to be supporting, which is also not met (HCI prior = 0.0035, far below the >0.68 threshold). Details ▾Hide ▴
PP3 The HCI prior probability of pathogenicity for c.630G>A (p.M210I) is 0.0035, as reported in the local HCI-PRIORS-MSH2 lookup table. This value is well below the VCEP PP3_supporting threshold of >0.68. SpliceAI delta score is 0.04, below the 0.2 threshold for non-canonical splice prediction. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0035 (<0.68 threshold for PP3_supporting). SpliceAI max delta = 0.04 (<0.2).
Sources
BA1 The VCEP BA1 threshold requires gnomAD v4 grpmax filtering allele frequency ≥ 0.001 (0.1%). The observed grpmax FAF is 4.369e-05, far below this threshold. This variant is too rare in population databases to qualify as a common benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 4.369e-05
- far below BA1 threshold of ≥0.001.
Sources
BS1 The VCEP BS1 threshold requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0001 (0.01%). The observed grpmax FAF is 4.369e-05, which is below this threshold. The variant does not meet the population frequency cutoff for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 4.369e-05
- below BS1 threshold of ≥0.0001.
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo data are available for this variant. No reports of confirmed de novo occurrence of NM_000251.3:c.630G>A with maternity and paternity confirmed were found in ClinVar, the literature packet, or the evidence brief. Details ▾Hide ▴
Evidence considered
- No de novo observations reported for this variant.
Still missing
- De novo status has not been evaluated for this variant. If de novo observations become available
- PS2 may become applicable.
Sources
PS3 PMID 33357406 (Jia et al. 2021) provides a calibrated functional assay via deep mutational scanning of MSH2 recognized by the InSiGHT MMR VCEP SVI documentation (22 P/LP validation controls, LOF score threshold >0.4 for abnormal readout). However, the variant NM_000251.3:c.630G>A (p.M210I) is not individually reported in the full-text narrative, and its specific LOF score or calibrated functional odds could not be retrieved from the available data. Without the variant-specific functional score, PS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- PMID 33357406 describes a calibrated functional assay for MSH2 missense variants but does not individually report functional data for p.M210I.
Still missing
- The LOF score for p.M210I from the Jia et al. (2021) deep mutational scan should be retrieved from the study's supplementary data to determine whether PS3/BS3 applies.
Sources
PMID:33357406 ↗vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for this variant. No pedigree information or Bayes likelihood ratios for co-segregation were found in the case evidence, ClinVar submissions, or literature. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- Co-segregation analysis in affected families would be required to assess PP1.
Sources
PP4 No tumor MSI/IHC data are available for this variant. The VCEP PP4 criterion requires evidence of MSI-H colorectal/endometrial tumors and/or loss of MMR protein expression consistent with MSH2 variant location. No such clinical data were provided in the case evidence, ClinVar submissions, or literature. Details ▾Hide ▴
Evidence considered
- No tumor pathology data available for PP4 assessment.
Still missing
- Tumor MSI status and IHC for MSH2/MSH6 protein expression would be required to assess PP4.
Sources
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH2 variant was found. The VCEP BS2 rule requires confirmed phase with a pathogenic variant in trans in a patient with colorectal cancer after age 45 (or other LS cancer above median age of onset) without CMMRD features. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data available.
Still missing
- Phase-confirmed co-occurrence data would be needed to assess BS2.
Sources
BS3 PMID 33357406 (Jia et al. 2021) provides a calibrated functional assay for MSH2 recognized by the VCEP SVI documentation. However, the specific functional odds or LOF score for p.M210I were not retrievable from the full text. Without the variant-specific calibrated functional readout, BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- PMID 33357406 describes a calibrated functional assay but does not individually report functional data for p.M210I.
Still missing
- The LOF score for p.M210I from the Jia et al. (2021) deep mutational scan supplementary data should be retrieved. If the functional odds ≤0.05 (BS3_Strong) or ≤0.48 (BS3_Supporting)
- BS3 would apply.
Sources
PMID:33357406 ↗vcep_functional_assay_svi_documentation_mmr
BS4 No segregation data demonstrating lack of co-segregation with disease are available. VCEP BS4 requires pedigree-based Bayes likelihood ratios showing lack of co-segregation. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Pedigree data with affected and unaffected carriers would be needed to assess BS4.
BP5 No tumor data are available demonstrating MSS status or no loss of MMR protein expression. The VCEP BP5 criterion requires tumor evidence inconsistent with the variant causing disease (MSS tumors, no loss of MMR expression, BRAF V600E/MLH1 methylation in context). Details ▾Hide ▴
Evidence considered
- No tumor data available for BP5 assessment.
Still missing
- Tumor pathology data (MSI status
- IHC) would be needed to assess BP5.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000251.3:c.630G>A is a missense variant (p.Met210Ile). PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites) per the InSiGHT MMR VCEP v2.0 decision tree. This substitution does not fall into any PVS1-eligible variant bucket. Details ▾Hide ▴
Evidence considered
- Missense variants are excluded from PVS1 application under the VCEP PVS1 decision tree for MMR genes.
Sources
PS4 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks PS4 as Not Applicable for MMR variant classification, citing the availability of tumor IHC data through PP4 as the preferred approach. Details ▾Hide ▴
PM1 VCEPThe InSiGHT MMR VCEP v2.0 explicitly states PM1 is Not Applicable: '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 ▴
PM6 VCEPThe InSiGHT MMR VCEP v2.0 marks PM6 as Not Applicable. De novo evidence is assessed through PS2 in this framework. Details ▾Hide ▴
Evidence considered
- VCEP specification: PM6 not applicable
- de novo evidence handled via PS2.
Sources
PP2 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks PP2 as Not Applicable: 'Missense variant in a gene with low rate of benign missense changes does not apply.' Details ▾Hide ▴
PP5 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks PP5 as 'Not Applicable for this VCEP' per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, so PP5 would not be met even under a generic fallback. Details ▾Hide ▴
BP1 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks BP1 as Not Applicable: 'Missense variant in a gene where only loss of function causes disease is not applicable.' Details ▾Hide ▴
BP2 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks BP2 as Not Applicable. BS2 is used instead for co-occurrence evidence. Details ▾Hide ▴
BP6 VCEPThe InSiGHT MMR VCEP v2.0 explicitly marks BP6 as 'Not Applicable for this VCEP' per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, so BP6 would not be met even under generic fallback. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification. NM_000251.3:c.630G>A is a missense variant (p.Met210Ile) and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7 is restricted to synonymous and intronic variants. This is a missense substitution.
Sources
PS5 N/APS5 is not part of the InSiGHT MMR VCEP specification v2.0. The criterion is not used by this expert panel framework. Details ▾Hide ▴
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.630G>A
- Protein (HGVS p.)
- NP_000242.1:p.(Met210Ile)
- GRCh38
- chr2:47410357 G>A
- GRCh37
- chr2:47637496 G>A
- ClinVar
- 577710
- COSMIC
- COSV113236220
Gene diagram
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.
MSH2NM_000251.3
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 MSH2
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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
10 / 1,613,900 alleles
AF 6.2e-06 · 0 homozygotes · FAF 4.37e-05
gnomAD v2.1
2 / 250,642 alleles
AF 7.98e-06 · 0 homozygotes · FAF 1.08e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-06 · 10 / 1,613,900 alleles · 0 hom · FAF 4.4e-05
| South Asian8 / 91,066 | 8.8e-05 |
| Remaining individuals1 / 62,486 | 1.6e-05 |
| European (non-Finnish)1 / 1,180,024 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 250,642 alleles · 0 hom · FAF 1.1e-05
| South Asian2 / 30,616 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19617e-06; MAF= 0.00062%, 10/1613900 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.78484e-05; MAF= 0.00878%, 8/91066 alleles, homozygotes = 0); grpmax FAF= 4.369e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.97951e-06; MAF= 0.00080%, 2/250642 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53253e-05; MAF= 0.00653%, 2/30616 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.400
- BayesDel
- -0.059
How the predictions were used
BP4 SupportingThe HCI prior probability of pathogenicity for c.630G>A (p.M210I) is 0.0035, which is below the VCEP BP4_supporting threshold of <0.11. This indicates that computational evidence predicts no damaging effect on the gene product, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.0035
- well below the VCEP BP4_supporting threshold of <0.11. SpliceAI max delta = 0.04 (<0.1) confirms no predicted splicing impact.
Sources
hci_priorcspec ↗
PP3 The HCI prior probability of pathogenicity for c.630G>A (p.M210I) is 0.0035, as reported in the local HCI-PRIORS-MSH2 lookup table. This value is well below the VCEP PP3_supporting threshold of >0.68. SpliceAI delta score is 0.04, below the 0.2 threshold for non-canonical splice prediction. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0035 (<0.68 threshold for PP3_supporting). SpliceAI max delta = 0.04 (<0.2).
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 per the VCEP specification. NM_000251.3:c.630G>A is a missense variant (p.Met210Ile) and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7 is restricted to synonymous and intronic variants. This is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.4. BayesDel score = -0.0594243. HCI prior probability for pathogenicity = 0.0035. MAPP score = 4.66. Custom PP2 score = 0.016.
3 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 33357406 ↗Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.Jia X et al. · 2021Jia et al. performed deep mutational scanning of MSH2 via chemical selection for MMR dysfunction with deep sequencing readout, generating a nearly complete functional effect map covering 94.4% of all possible MSH2 missense variants. The assay is recognized as a calibrated functional assay by the InSiGHT MMR VCEP (22 P/LP validation controls, LOF score >0.4 threshold for abnormal readout). The study provides strong concordance with existing functional data (95.8%) and expert-reviewed ClinVar/InSiGHT classifications (95.4% specificity/sensitivity).Does not name this variant
Quoted passage
The resulting functional effect map was substantially complete, covering 94.4% of possible MSH2 single-codon substitutions.
Full text reviewed; variant not found in narrative. Individual scores are available in supplementary data not included in the case folder.
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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. · 2015ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. Lynch syndrome and MMR genes (including MSH2) are discussed at the gene level for clinical referral criteria. No variant-specific data for NM_000251.3:c.630G>A were identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Nykamp et al. describe the Sherloc framework for refining ACMG-AMP variant classification criteria. The paper provides a systematic approach to evidence weighting and criterion application. No variant-specific data for NM_000251.3:c.630G>A were identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
10 / 1,613,900 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
1 Likely benign · 1 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/1577628936
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/577710/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47637496-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47410357-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47410357-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.630G…
- OncoKB ↗www.oncokb.org/gene/MSH2/M210I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124535427
- 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= 6.19617e-06; MAF= 0.00062%, 10/1613900 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.78484e-05; MAF= 0.00878%, 8/91066 alleles, homozygotes = 0); grpmax FAF= 4.369e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.97951e-06; MAF= 0.00080%, 2/250642 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53253e-05; MAF= 0.00653%, 2/30616 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 577710)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.4. BayesDel score = -0.0594243. HCI prior probability for pathogenicity = 0.0035. MAPP score = 4.66. 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. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV113236220, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.