Starting
Initialising…
0%
MSH2
Final classification
VUS
MSH2 c.2197G>A · p.Ala733Thr
MSH2

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.

Gene
MSH2
Transcript
NM_000251.3
HGVS · transcript:coding
NM_000251.3:c.2197G>A
Consequence
N/A
GRCh38
chr2:47476558 G>A
GRCh37
chr2:47703697 G>A
Basis 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.
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.
Classification rationale
BS1 VUS
MSH2 c.2197G>A

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.1 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).2 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).3 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.4 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.5 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.6

BS1 VUS
4 cspec ↗pvs1_variant_assessment
5 cspec ↗vcep_functional_assay_svi_documentation_mmr
Gene diagram · NM_000251.3 · variants mapped to exon structure
MSH2 NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      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.
      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.
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0036% · 58 / 1,614,108
      0 hom · FAF 0.033%
      East Asian
      22 / 44,880
      0.049%
      Remaining individuals
      11 / 62,508
      0.018%
      South Asian
      16 / 91,076
      0.018%
      European (non-Finnish)
      9 / 1,180,008
      0.00076%
      + 6 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0048% · 12 / 251,444
      0 hom · FAF 0.014%
      East Asian
      6 / 18,394
      0.033%
      South Asian
      6 / 30,616
      0.02%
      + 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      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)
      SpliceAI screenshot
      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 screenshot
      Functional Unknown Oncogenic Effect
      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.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51876328, n = 3 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 11 PMIDs not cited in assessment
      22006311 ↗ Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. CLINVAR
      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. CLINVAR
      26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
      31386297 ↗ Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients. CLINVAR
      32547938 ↗ Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. CLINVAR
      33357406 ↗ Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. CLINVAR
      38509102 ↗ Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China. CLINVAR
      24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
      22964825 ↗ Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR
      28706299 ↗ Findings of a 1303 Korean whole-exome sequencing study. CLINVAR