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 ↗

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 · 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