MSH2 c.100G>A, p.Val34Met
NM_000251.3:c.100G>A
COSMIC ID: COSM9113507
Variant of Uncertain Significance (VUS)
MSH2 c.100G>A (V34M) remains classified as VUS. PM2 (Supporting) and BP4 (Supporting) are the only applicable criteria; no additional pathogenic or benign evidence is available to shift classification.
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.100G>A
Protein Change
V34M
Location
Exon 1
(Exon 1 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 34 in gene MSH2
Alternate Identifiers
COSM9113507
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.100G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000896%
Very Rare
Highest in Population
East Asian
0.012%
Low Frequency
Global: 0.000896%
East Asian: 0.012%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 223268Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000896%, 2/223268 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.012%, 2/16614 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This missense variant replaces valine with methionine at codon 34 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 has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in a pancreatic cancer case-control study as present in 13 unaffected individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 2/223268 chromosomes 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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This missense variant replaces valine with methionine at codon 34 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). In a pancreatic cancer case-control study, this variant has been reported in 0/1005 pancreatic cancer cases and 13/23705 controls (PMID: 32980694). This variant has been identified in 2/223268 chromosomes 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.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Likely benign (2 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 34 in gene MSH2
Functional Summary
The MSH2 V34M variant has not been functionally characterized, and its biological significance is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.08
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 Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2...". The evidence for this variant shows: NM_000251.3:c.100G>A is a missense change (V34M), not a null variant. Therefore, this criterion is not applied because the variant is not a null (loss‐of‐function) variant.
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: no other MSH2 variant with V34M has been classified as Pathogenic. Therefore, this criterion is not applied because there is no established pathogenic variant encoding the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Evidence of de novo occurrence in a patient with the disease (with confirmation of paternity and maternity)." The evidence for this variant shows: no data on de novo status. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional assay data.
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 prevalence data. Therefore, this criterion is not applied due to lack of case–control evidence.
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: no evidence that codon 34 of MSH2 lies in a defined mutational hot spot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: MAF in gnomAD = 0.000896% (≈1 in 111,600 alleles), meeting the <1 in 50,000 threshold. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on zygosity or co‐occurrence with a pathogenic variant. Therefore, this criterion 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 or stop‐loss variants." The evidence for this variant shows: V34M is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change was classified as Pathogenic." The evidence for this variant shows: no other missense at residue 34 has been classified as Pathogenic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting Strength: Assumed de novo, but without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members." The evidence for this variant shows: no familial segregation data. Therefore, this criterion 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 low rate of benign missense variation and missense is a common mechanism of disease." The evidence for this variant shows: MSH2 has known pathogenic missense variants and benign missense variation; no data to support PP2. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Missense variant with HCI‐prior probability >0.68 & ≤0.81 OR predicted splice defect with SpliceAI delta ≥0.2." The evidence for this variant shows: mixed in silico predictions and SpliceAI delta ≤0.1. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Strength: One CRC/Endometrial MSI‐H tumor with loss of MMR protein expression consistent with variant location." The evidence for this variant shows: no tumor or IHC data. Therefore, this criterion 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 without evidence." The evidence for this variant shows: ClinVar submissions are VUS or Likely Benign. Therefore, this criterion 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: MAF = 0.000896%, below the 0.1% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: GnomAD v4 grpmax frequency ≥0.0001 & <0.001." The evidence for this variant shows: MAF = 0.00000896, below the 0.0001 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed in trans with a pathogenic variant in LS gene in a healthy individual." The evidence for this variant shows: no co‐occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well‐established functional studies show no damaging effect." The evidence for this variant shows: no functional assays performed. Therefore, this criterion 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 of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: MSH2 pathogenic variants include missense changes. Therefore, this criterion 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 for a dominant disorder." The evidence for this variant shows: no trans co‐occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows: V34M is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Missense variant with HCI-prior probability <0.11 OR SpliceAI predicts no splicing impact (delta ≤0.1)." The evidence for this variant shows: SpliceAI predicts no splicing impact and in silico tools are mixed. Therefore, this criterion is applied at Supporting strength because computational evidence suggests no splicing or functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such cases. Therefore, this criterion 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 without available evidence." The evidence for this variant shows: ClinVar submissions include Likely Benign but not from expert panels. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant with no predicted splicing impact." The evidence for this variant shows: V34M is a missense, not synonymous. Therefore, this criterion is not applied.