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LYFE SCIENCES
Project: HERA
NM_000251.3:c.67T>C
p.Phe23Leu  ·  MSH2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PP4
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueF23
Hotspots ↗