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
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.
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
BS1
→
VUS
3
hci_priorspliceai ↗cspec ↗
4
cspec ↗pvs1_variant_assessment
5
cspec ↗vcep_functional_assay_svi_documentation_mmr
6
cspec ↗
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
gnomAD v2.1
Population frequency
Overall AF
58 / 1,614,108
0.0036%
Highest · East Asian
0.049%
Homozygotes
0
grpmax FAF
0.033%
Allele frequency by ancestry — gnomAD v4.1
observed in 3 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 22 / 44,880 | 0.049% | 0 |
| South Asian | 16 / 91,076 | 0.018% | 0 |
| European (non-Finnish) | 9 / 1,180,008 | 0.00076% | 0 |
| Admixed American | 0 / 60,014 | — | — |
| European (Finnish) | 0 / 64,028 | — | — |
| Amish | 0 / 912 | — | — |
| Middle Eastern | 0 / 6,052 | — | — |
| Ashkenazi Jewish | 0 / 29,604 | — | — |
| African/African American | 0 / 75,026 | — | — |
“
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.
Overall AF
12 / 251,444
0.0048%
Highest · East Asian
0.033%
Homozygotes
0
grpmax FAF
0.014%
Allele frequency by ancestry — gnomAD v2.1
observed in 2 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 6 / 18,394 | 0.033% | 0 |
| South Asian | 6 / 30,616 | 0.02% | 0 |
| African/African American | 0 / 16,256 | — | — |
| Admixed American | 0 / 34,592 | — | — |
| Ashkenazi Jewish | 0 / 10,076 | — | — |
| European (Finnish) | 0 / 21,648 | — | — |
| European (non-Finnish) | 0 / 113,726 | — | — |
| Remaining individuals | 0 / 6,136 | — | — |
“
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.
“
This variant is absent from gnomAD-Canada.
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
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.
COSMIC
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.
Literature · 23 PMIDs triaged · 8 high-priority
23papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
22006311 ↗
functional
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopia
BS3PP5PS3PS4
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
31386297 ↗
functional
Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.
Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome-wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients. Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2)
BS3PP5PS3PS4
32547938 ↗
functional
Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.
Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We p
BS3PP5PS3PS4
33357406 ↗
functional
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.
The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed "variants of uncertain significance" (VUS). To systematically resolve their functional
BS3PP5PS3PS4
38509102 ↗
functional
Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.
DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize ge
BS3PP5PS3PS4
24493721 ↗
case observation
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
PP5PS4
22964825 ↗
background review
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links