Classification rationale

BA1 Benign

MSH2 c.67T>C

The MSH2 c.67T>C (p.Phe23Leu) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar predominantly as benign or likely benign, with an aggregate ClinVar classification of Benign.¹ This variant is present at high frequency in population databases, including gnomAD v4.1 at 410/1600398 alleles with 8 homozygotes and grpmax filtering allele frequency 0.00394201, which exceeds the MSH2 VCEP BA1 threshold.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01; no missense-specific HCI prior value was available to support PP3 or BP4 assessment.³

BA1 → Benign

1 cosmicclinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗

3 spliceai ↗

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.

Gene diagram · NM_000251.3 · variants mapped to exon structure

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BA1 Stand Alone review Benign

The variant exceeds the MSH2 VCEP BA1 frequency threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.00394201, above the BA1 cutoff of 0.001, with 410/1600398 alleles observed overall and 8 homozygotes. No founder pathogenic exception was identified in the reviewed sources.

gnomAD v4.1 grpmax FAF 0.00394201; total AF 0.000256186; 410/1600398 alleles; 8 homozygotesHighest observed subpopulation frequency in gnomAD v4.1 is 1KG:BEB AF 0.020202 (4/198 alleles)ClinVar aggregate interpretation is Benign with multiple benign/likely benign submissions

gnomad_v4 ↗gnomad_v2 ↗clinvar ↗

Assessed · not applied · 2 not met · 13 not assessed

Pathogenic

PP4 No individual tumor MSI/IHC or phenotype data were identified to support PP4 under the MSH2 VCEP rules.

PM5 No evidence was identified in the reviewed sources for a different pathogenic or likely pathogenic missense change at residue Phe23 that would satisfy PM5, and PP3 was not established.

PM2 The variant is not absent or extremely rare in population databases; gnomAD v4.1 shows total AF 0.000256186 with grpmax FAF 0.00394201, well above the PM2_Supporting threshold of <0.00002.

PS1 No prior pathogenic or likely pathogenic nucleotide change encoding the same amino acid substitution was identified in the reviewed sources.

PS2 No de novo data were identified.

PP1 No segregation data or Bayes likelihood ratio were identified to support co-segregation.

PS3 No variant-specific calibrated functional assay or qualifying MMR functional flowchart evidence demonstrating an MMR defect was identified for p.Phe23Leu.

PP3 For MSH2 missense variants, PP3 requires an HCI prior probability >0.68; no HCI prior value was identified.

PM3 No biallelic observation data or point-based PM3 evidence were identified.

Benign

BS4 No segregation data or Bayes likelihood ratio were identified.

BS3 No variant-specific calibrated functional assay or qualifying RNA assay demonstrating proficient function was identified.

BP4 For MSH2 missense variants, BP4 requires an HCI prior probability of pathogenicity <0.11; no HCI prior value was identified.

BS1 The population frequency exceeds the BS1 range and instead falls into the BA1 range.

BP5 No tumor data showing MSS, retained MMR protein expression, or gene-inconsistent IHC loss were identified.

BS2 No confirmed in trans co-occurrence with a known pathogenic MSH2 variant in an appropriately phenotyped older individual was identified.

N/A · 12 BP3 · BP7 · BP2 · BP6 · PM1 · PP5 · PM6 · PVS1 · PS4 · PM4 · BP1 · PP2

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000256186; MAF= 0.02562%, 410/1600398 alleles, homozygotes = 8) and has highest observed frequency in the 1KG:BEB population (AF= 0.020202; MAF= 2.02020%, 4/198 alleles, homozygotes = 0); grpmax FAF= 0.00394201.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000559062; MAF= 0.05591%, 141/252208 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00480596; MAF= 0.48060%, 133/27674 alleles, homozygotes = 2); grpmax FAF= 0.00414111.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.026% · 410 / 1,600,398
8 hom · FAF 0.39%

1KG:BEB 4 / 198	2%
1KG:STU 2 / 196	1%
1KG:ITU 1 / 204	0.49%
South Asian 388 / 88,660	0.44% 8 hom
1KG:XY 5 / 2,492	0.2%
1KG:XX 2 / 2,476	0.081%
Remaining individuals 21 / 62,004	0.034%
African/African American 1 / 74,948	0.0013%

+ 30 not observed (Admixed American, European (Finnish), Middle Eastern, European (non-Finnish), Ashkenazi Jewish, East Asian, Amish, 1KG:ESN, 1KG:PUR, 1KG:PJL, 1KG:CLM, 1KG:JPT, 1KG:CHB, 1KG:TSI, 1KG:MXL, 1KG:CEU, 1KG:MSL, 1KG:YRI, 1KG:FIN, 1KG:KHV, 1KG:CDX, 1KG:LWK, 1KG:ACB, 1KG:ASW, 1KG:IBS, 1KG:GBR, 1KG:PEL, 1KG:GIH, 1KG:CHS, 1KG:GWD)

gnomAD v2.1

0.056% · 141 / 252,208
2 hom · FAF 0.41%

South Asian 133 / 27,674	0.48% 2 hom
Remaining individuals 7 / 6,528	0.11%
European (non-Finnish) 1 / 114,224	0.00088%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots

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