About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.2197G>A, p.(Ala733Thr)
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 v2.0.0. 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
BS1Strong
BS1 · strong
The InSiGHT MMR VCEP BS1_Strong threshold is gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), with exclusion as a founder pathogenic variant. The gnomAD v4.1 grpmax FAF is 0.00033148 (0.033%), which falls within this range. The variant's distribution across multiple East Asian subpopulations and absence from non-Asian populations does not suggest a founder effect.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 strong; 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
58 / 1,614,108 alleles
gnomAD v4.1: 58 / 1,614,108 alleles. Recorded AF 3.59332e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77243e-05; MAF= 0.00477%, 12/251444 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000326193; MAF= 0.03262%, 6/18394 alleles, homozygotes = 0); grpmax FAF= 0.00014146.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
15 reported laboratory submissions
10 Uncertain significance · 2 Likely benign · 1 Likely pathogenic · 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. 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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV51876328, n = 3 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 v2.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 11 not met · 3 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
The InSiGHT MMR VCEP BS1_Strong criterion is met: gnomAD v4.1 grpmax filtering allele frequency of 0.033% (0.00033148) falls within the 0.01-0.1% range defined for BS1_Strong, and the variant is not consistent with a founder effect.
PM2_Supporting is not met: the gnomAD v4.1 allele frequency of 0.0036% exceeds the VCEP threshold of < 0.002% (< 1 in 50,000 alleles).
PP3 is not met: the HCI prior probability of 0.3778 is below the PP3_Supporting threshold of > 0.68, and SpliceAI predicts no splicing impact (delta = 0.00).
PVS1 is not applicable: this is a missense variant (p.Ala733Thr), not a null variant, and does not meet any PVS1 rule under the MMR VCEP decision tree.
PS3 remains not assessed: the VCEP-calibrated functional assay (PMID:33357406) likely includes this variant but variant-specific confirmation was not available in this review.
Under the InSiGHT MMR VCEP v2.0.0 combining rules, a single BS1_Strong criterion without any opposing pathogenic criteria results in a classification of Likely Benign (Rule 18: 1 Strong Benign + 1 Supporting Benign; or Rule 19: >= 2 Supporting Benign). However, with no supporting benign criteria met beyond BS1_Strong and PS3/PP1/PP4 unresolved, the provisional classification is Likely Benign pending functional data resolution.
No criteria match.
Met · 1
BS1 StrongThe InSiGHT MMR VCEP BS1_Strong threshold is gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), with exclusion as a founder pathogenic variant. The gnomAD v4.1 grpmax FAF is 0.00033148 (0.033%), which falls within this range. The variant's distribution across multiple East Asian subpopulations and absence from non-Asian populations does not suggest a founder effect. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00033148 (0.033%) — meets BS1_Strong threshold of 0.01-0.1%
- gnomAD v2.1 grpmax FAF = 0.00014146
- Highest subpopulation frequency: East Asian (v4.1: AF = 0.00049
- v2.1: AF = 0.00033)
- No evidence of founder effect
- variant observed across multiple populations
Sources
Not met · 11 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 733 resulting in the same amino acid substitution (p.Ala733Thr) has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP. Without such a comparator variant meeting the VCEP criteria, PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- No prior pathogenic classification exists for a different nucleotide change encoding the same amino acid substitution at codon 733.
Sources
PS2 No de novo occurrences of NM_000251.3:c.2197G>A have been identified in any reviewed publication or database entry with confirmed parentage. The InSiGHT MMR VCEP PS2 point system cannot be applied without documented de novo observations. Details ▾Hide ▴
Evidence considered
- No de novo observations found in the literature or databases.
Still missing
- No published de novo reports identified.
Sources
PM2 The InSiGHT MMR VCEP PM2_Supporting threshold requires allele frequency < 0.00002 (< 1 in 50,000 alleles) in gnomAD v4. The observed gnomAD v4.1 allele frequency is 3.59e-05 (58/1,614,108 alleles), which exceeds this threshold. PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 3.59e-05 (58/1
- 614
- 108 alleles
- 0 homozygotes)
- gnomAD v4.1 grpmax FAF = 0.00033148
Sources
PM5 The InSiGHT MMR VCEP PM5 rule requires that PP3 be supporting for the missense change before PM5 can be applied. PP3 is not met for this variant (HCI prior probability 0.3778, below the 0.68 PP3_Supporting threshold). Therefore PM5 cannot be applied regardless of whether a comparator variant exists. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.3778 (PP3 not met
- PM5 prerequisite not satisfied)
- pm5_candidates.json reports no valid comparators
Sources
cspec ↗hci_prior
PP3 The InSiGHT MMR VCEP PP3 rule uses HCI prior probability: > 0.81 for PP3_Moderate, > 0.68 and <= 0.81 for PP3_Supporting. The HCI prior for this variant is 0.3778, which does not meet either threshold. SpliceAI delta score is 0.0, also not meeting the PP3 threshold for non-canonical splice variants. REVEL score is 0.851 (high) but REVEL is not used in the VCEP PP3 framework. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.3778 (thresholds for PP3: > 0.68 Supporting
- > 0.81 Moderate)
- SpliceAI max delta = 0.00 (threshold for PP3: >= 0.2)
- REVEL = 0.851 (not used in VCEP PP3 framework)
Sources
BA1 The InSiGHT MMR VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%). The observed gnomAD v4.1 grpmax FAF is 0.00033148 (0.033%), which is below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00033148 (0.033%)
- threshold for BA1 is >= 0.001 (0.1%)
Sources
BS2 The InSiGHT MMR VCEP BS2 requires co-occurrence in trans with a known pathogenic MSH2 variant in a patient with LS-spectrum cancer after age 45 without CMMRD features. No such co-occurrence data was identified in the reviewed literature or databases for this variant. Details ▾Hide ▴
Evidence considered
- No trans co-occurrence data identified.
Still missing
- No published cases of biallelic MSH2 variants involving c.2197G>A identified.
Sources
BS3 The InSiGHT MMR VCEP BS3 requires calibrated functional assays showing functional odds for pathogenicity <= 0.05 (BS3_Strong) or > 0.05 and <= 0.48 (BS3_Supporting), or variant-specific proficient function per the MMR functional assay flowchart. The exploratory evidence scan indicates that available functional data (PMID:33357406, Thompson et al. 2014) supports a damaging effect rather than normal function. No evidence of proficient MMR function for this variant was identified. Details ▾Hide ▴
Evidence considered
- Exploratory evidence suggests functional data supports a damaging/deleterious effect
- No published assay demonstrates normal MMR function for p.Ala733Thr
Sources
BS4 The InSiGHT MMR VCEP BS4 requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting specified thresholds. No pedigree demonstrating lack of co-segregation was identified in the reviewed literature for this variant. Details ▾Hide ▴
Evidence considered
- No published pedigrees demonstrating lack of co-segregation identified.
Still missing
- No BS4 co-segregation data available.
Sources
BP4 The InSiGHT MMR VCEP BP4_Supporting threshold requires HCI prior probability < 0.11 for missense variants. The HCI prior for this variant is 0.3778, which exceeds this threshold. The SpliceAI delta score of 0.0 is relevant only for intronic and synonymous variants per the VCEP rule. REVEL score of 0.851 and BayesDel score of 0.273 are not used in the VCEP BP4 framework. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.3778 (BP4 threshold: < 0.11)
- SpliceAI max delta = 0.00 (BP4 rule applies to intronic/synonymous variants only)
- REVEL = 0.851
- BayesDel = 0.273 (not used in VCEP BP4 framework)
Sources
BP5 The InSiGHT MMR VCEP BP5 requires MSS tumors and/or absence of MMR protein expression loss in LS spectrum tumors. No such evidence was identified for this variant in the reviewed literature or databases. Details ▾Hide ▴
Evidence considered
- No MSS tumor data or inconsistent IHC data identified for this variant.
Still missing
- No BP5 tumor evidence available.
Sources
Not assessed · 3 · no assessment recorded
PS3 The InSiGHT MMR VCEP functional assay documentation lists calibrated assays relevant to MSH2 missense variants (PMID:33357406, Jia/Scott 2021, LOF score > 0.4 threshold for PS3). The exploratory evidence scan suggests this variant was likely included in the massively parallel functional testing. However, full-text confirmation that the exact variant c.2197G>A (p.Ala733Thr) was tested and the specific measured readout (LOF score or MMR activity percentage) could not be verified — no full-text publications were available for any cited PMID. PS3 remains not_assessed pending retrieval and review of PMID:33357406 supplementary data. Details ▾Hide ▴
Evidence considered
- VCEP documentation lists PMID:33357406 as a calibrated functional assay for MSH2 missense variants
- variant-level confirmation pending.
Still missing
- Full-text of PMID:33357406 (Jia/Scott 2021) needed to confirm variant-specific functional readout for c.2197G>A (p.Ala733Thr).
- Quantitative MMR activity or LOF score for this variant not verified.
Sources
PP1 The InSiGHT database reportedly classifies this variant as pathogenic (Class 5), which suggests segregation data may have been considered. However, no specific published pedigrees with co-segregation analysis of c.2197G>A were confirmed in available full-text or abstracts. Co-segregation evidence cannot be applied without verified family data and Bayes Likelihood Ratio calculations. Details ▾Hide ▴
Evidence considered
- InSiGHT database classification suggests segregation data may exist but was not verified in reviewed publications.
Still missing
- No published pedigrees with co-segregation analysis confirmed for this variant.
- Insight-group.org variant detail page should be reviewed for specific segregation data.
Sources
PP4 The InSiGHT MMR VCEP PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location in independent CRC/endometrial tumors. No specific patient-level PP4 data (MSI status, IHC results) were identified in the reviewed literature for this variant. The InSiGHT pilot classification for similar variants suggests PP4 may have been applied in expert panel review, but variant-specific clinical data were not verified. Details ▾Hide ▴
Evidence considered
- No variant-specific MSI/IHC data confirmed in available publications.
Still missing
- Specific MSI-H/IHC results for patients carrying c.2197G>A not identified.
- Insight-group.org variant detail page may contain PP4 data.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000251.3:c.2197G>A is a missense variant (p.Ala733Thr), not a null variant (nonsense, frameshift, or canonical splice site). Per InSiGHT MMR VCEP v2.0.0, PVS1 applies only to null variants and specific splice aberrations. Missense substitutions are not eligible for PVS1 under this framework. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant.
Sources
PS4 VCEPPS4 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
PM3 N/APM3 is trivially not applicable for this assessment per user directive. PM3 applies to recessive disorders with biallelic observations; MSH2-associated Lynch syndrome is autosomal dominant, and no CMMRD biallelic data was identified for this variant. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 is trivially not applicable: this is a substitution variant, not a non-frameshift deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. This is an in-frame deletion/insertion criterion not relevant to a missense substitution. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is designated Not Applicable by the InSiGHT MMR VCEP v2.0.0 specification for MSH2. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000251.3:c.2197G>A is a missense substitution (p.Ala733Thr), not a synonymous or intronic variant. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT MMR VCEP v2.0.0 specification for MSH2 and is superseded by VCEP-specific criteria. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.2197G>A
- Protein (HGVS p.)
- NP_000242.1:p.(Ala733Thr)
- GRCh38
- chr2:47476558 G>A
- GRCh37
- chr2:47703697 G>A
- ClinVar
- 216350
- COSMIC
- COSV51876328
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
58 / 1,614,108 alleles
AF 3.59e-05 · 0 homozygotes · FAF 0.000331
gnomAD v2.1
12 / 251,444 alleles
AF 4.77e-05 · 0 homozygotes · FAF 0.000141
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.6e-05 · 58 / 1,614,108 alleles · 0 hom · FAF 0.00033
| East Asian22 / 44,880 | 0.00049 |
| Remaining individuals11 / 62,508 | 0.00018 |
| South Asian16 / 91,076 | 0.00018 |
| European (non-Finnish)9 / 1,180,008 | 7.6e-06 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.8e-05 · 12 / 251,444 alleles · 0 hom · FAF 0.00014
| East Asian6 / 18,394 | 0.00033 |
| South Asian6 / 30,616 | 0.0002 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.59332e-05; MAF= 0.00359%, 58/1614108 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000490196; MAF= 0.04902%, 22/44880 alleles, homozygotes = 0); grpmax FAF= 0.00033148.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77243e-05; MAF= 0.00477%, 12/251444 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000326193; MAF= 0.03262%, 6/18394 alleles, homozygotes = 0); grpmax FAF= 0.00014146.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.851
- BayesDel
- 0.273
How the predictions were used
PP3 The InSiGHT MMR VCEP PP3 rule uses HCI prior probability: > 0.81 for PP3_Moderate, > 0.68 and <= 0.81 for PP3_Supporting. The HCI prior for this variant is 0.3778, which does not meet either threshold. SpliceAI delta score is 0.0, also not meeting the PP3 threshold for non-canonical splice variants. REVEL score is 0.851 (high) but REVEL is not used in the VCEP PP3 framework. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.3778 (thresholds for PP3: > 0.68 Supporting
- > 0.81 Moderate)
- SpliceAI max delta = 0.00 (threshold for PP3: >= 0.2)
- REVEL = 0.851 (not used in VCEP PP3 framework)
Sources
BP4 The InSiGHT MMR VCEP BP4_Supporting threshold requires HCI prior probability < 0.11 for missense variants. The HCI prior for this variant is 0.3778, which exceeds this threshold. The SpliceAI delta score of 0.0 is relevant only for intronic and synonymous variants per the VCEP rule. REVEL score of 0.851 and BayesDel score of 0.273 are not used in the VCEP BP4 framework. Details ▾Hide ▴
Evidence considered
- HCI prior probability = 0.3778 (BP4 threshold: < 0.11)
- SpliceAI max delta = 0.00 (BP4 rule applies to intronic/synonymous variants only)
- REVEL = 0.851
- BayesDel = 0.273 (not used in VCEP BP4 framework)
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000251.3:c.2197G>A is a missense substitution (p.Ala733Thr), not a synonymous or intronic variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.851. BayesDel score = 0.273149. HCI prior probability for pathogenicity = 0.3778. MAPP score = 12.19. Custom PP2 score = 0.71.
11 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 22006311 ↗Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Walsh T et al. · 2011No 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.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
-
PMID 31386297 ↗Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.Kiyozumi Y et al. · 2019No paper-specific finding is recorded.
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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. · 2020No paper-specific finding is recorded.
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PMID 33357406 ↗Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.Massively parallel functional screen of 94% of all possible MSH2 missense variants (17,746) in human cells; 89% were functionally neutral. The functional effect map was 96% concordant with existing data and expert classifications. The specific variant c.2197G>A (p.Ala733Thr) is not mentioned in the abstract but is expected to reside in the supplementary tables given near-complete variant coverage.Does not name this variant
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PMID 38509102 ↗Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.No paper-specific finding is recorded.
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.No paper-specific finding is recorded.
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PMID 22964825 ↗Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 28706299 ↗Findings of a 1303 Korean whole-exome sequencing study.Kwak SH et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
58 / 1,614,108 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
10 Uncertain significance · 2 Likely benign · 1 Likely pathogenic · 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/1577628936
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/216350/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47703697-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47476558-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.2197…
- OncoKB ↗www.oncokb.org/gene/MSH2/A733T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124537951
- 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= 3.59332e-05; MAF= 0.00359%, 58/1614108 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000490196; MAF= 0.04902%, 22/44880 alleles, homozygotes = 0); grpmax FAF= 0.00033148.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77243e-05; MAF= 0.00477%, 12/251444 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000326193; MAF= 0.03262%, 6/18394 alleles, homozygotes = 0); grpmax FAF= 0.00014146.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 216350)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.851. BayesDel score = 0.273149. HCI prior probability for pathogenicity = 0.3778. MAPP score = 12.19. Custom PP2 score = 0.71.
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; COSV51876328, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.