MSH2 c.448G>A, p.Val150Ile
NM_000251.3:c.448G>A
COSMIC ID: COSM9496206
Variant of Uncertain Significance (VUS)
The MSH2 p.V150I missense variant is absent from population databases (PM2) and predicted benign by multiple in silico tools with no splicing impact (BP4). No supporting functional, segregation, tumor, or case-control evidence is available. The combination of limited evidence yields a classification of VUS.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
MSH2
Transcript
NM_000251.3
MANE Select
Total Exons
16
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 16 exons | Forward |
| NM_000251.1 | Alternative | 16 exons | Forward |
Variant Details
HGVS Notation
NM_000251.3:c.448G>A
Protein Change
V150I
Location
Exon 3
(Exon 3 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 150 in gene MSH2
Alternate Identifiers
COSM9496206
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.448G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
3 publications
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This missense variant replaces valine with isoleucine at codon 150 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been observed in a cohort of individuals affected with prostate cancer (PMID: 31874108). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 150 of the MSH2 protein (p.Val150Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 582751). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 150 in gene MSH2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metalr: D
Benign:
CADD: 0.46polyphen_prediction: benignmetasvm: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2...". The evidence for this variant shows: NM_000251.3:c.448G>A is a missense change (p.V150I), not a null or splice-site variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic...". The evidence for this variant shows: p.V150I has not been previously established as pathogenic via any nucleotide change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong: ≥4 de novo points; Strong: 2–3 de novo points; Moderate: 1 de novo point; Supporting: 0.5 de novo points.". The evidence for this variant shows: de novo status has not been assessed (no parental testing). Therefore, PS2 is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7; Moderate: assays with odds >4.3 ≤18.7; Supporting: odds >2.08 ≤4.3.". The evidence for this variant shows: no functional studies have been performed on MSH2 p.V150I. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls.". The evidence for this variant shows: no case–control or segregation prevalence data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation.". The evidence for this variant shows: p.V150I is not located in a known critical functional domain or hotspot. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.". The evidence for this variant shows: NM_000251.3:c.448G>A is not found in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Points for variants detected in trans with a pathogenic variant in recessive disorders.". The evidence for this variant shows: no data on in trans occurrence with a pathogenic MSH2 variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame deletions/insertions in a non-repeat region or stop‐loss variants.". The evidence for this variant shows: p.V150I is a missense substitution, not an in‐frame indel. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic.". The evidence for this variant shows: no other pathogenic missense changes at codon 150 in MSH2. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting: Unconfirmed de novo occurrence.". The evidence for this variant shows: de novo status is unassessed. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong co‐segregation evidence based on Bayes LR thresholds.". The evidence for this variant shows: no family segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism.". The evidence for this variant shows: MSH2 has both truncating and missense pathogenic variants. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Moderate: HCI prior probability >0.81; Supporting: HCI >0.68≤0.81 or SpliceAI ≥0.2.". The evidence for this variant shows: mixed in silico predictions and SpliceAI delta score 0.02. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Tumor phenotype with MSI‐H and/or loss of MMR protein expression consistent with variant location.". The evidence for this variant shows: no tumor or IHC data. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic.". The evidence for this variant shows: ClinVar entries all list Uncertain Significance. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%).". The evidence for this variant shows: allele frequency = 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: allele frequency ≥0.0001 and <0.001 in gnomAD v4.". The evidence for this variant shows: allele frequency = 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: observed in trans with a known pathogenic variant in a healthy individual.". The evidence for this variant shows: no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: calibrated functional assays with odds ≤0.05; Supporting: odds >0.05≤0.48.". The evidence for this variant shows: no functional assays. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members.". The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease.". The evidence for this variant shows: MSH2 pathogenic variants include missense changes. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant disorder.". The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indels in a repetitive region.". The evidence for this variant shows: p.V150I is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variant with HCI‐prior probability <0.11 or SpliceAI delta score ≤0.1.". The evidence for this variant shows: mixed in silico predictions overall benign and SpliceAI 0.02. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Tumors inconsistent with Lynch syndrome phenotype.". The evidence for this variant shows: no tumor data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign.". The evidence for this variant shows: no such reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splicing impact.". The evidence for this variant shows: p.V150I is a missense change. Therefore, BP7 is not applied.