MSH2 c.128A>G, p.Tyr43Cys
NM_000251.3:c.128A>G
COSMIC ID: COSM9497214
Variant of Uncertain Significance (VUS)
This MSH2 c.128A>G (p.Y43C) variant remains a VUS. Only PP3 (supporting computational evidence) is met; all other ACMG criteria are not applicable or lack data under MSH2-specific VCEP guidelines.
ACMG/AMP Criteria Applied
PP3
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.128A>G
Protein Change
Y43C
Location
Exon 1
(Exon 1 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 43: Y43F
Alternate Identifiers
COSM9497214
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.128A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00727%
Rare
Highest in Population
European (non-Finnish)
0.016%
Low Frequency
Global: 0.00727%
European (non-Finnish): 0.016%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 261262Alt: 19Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00727%, 19/261262 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.016%, 19/118526 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
6 publications
Uncertain Significance (VUS)
Based on 18 submitter reviews in ClinVar
Submitter Breakdown
10 VUS
7 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (6)
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.
Variant summary: MSH2 c.128A>G (p.Tyr43Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 1605788 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00012 vs 0.00057), allowing no conclusion about variant significance. The variant, c.128A>G, has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome and with other tumor phenotypes, which were mostly outside of the Lynch syndrome tumor spectrum (e.g. Schmitt_2002, Auclair_2006, Aloraifi_2015, Zhang_2015, Chan_2018, Dominguez-Valentin_2018, Sehdev_2018, Li_2020, Dorling_2021), but was also found in several healthy controls (e.g. Dorling_2021). Co-occurrence with another pathogenic variant has been reported (MSH6 c.2405del, p.802LeufsX7 in the UMD database) for this variant. Multiple publications reported experimental evidence evaluating an impact on protein function, and all of them demonstrated no damaging effect for this variant (Auclair_2006, Bouvet_2019, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 26250988, 16395668, 30998989, 30093976, 18383312, 29458332, 33471991, 33357406, 31391288, 30131383, 26580448). ClinVar contains an entry for this variant (Variation ID: 90619). Based on the evidence outlined above, the variant was classified as likely benign.
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
The MSH2 c.128A>G (p.Tyr43Cys) variant has been reported in the published literature in individuals affected with breast cancer (PMIDs: 35264596 (2022), 31569399 (2019)), pancreatic cancer (PMID: 30131383 (2018)), and colorectal cancer (PMID: 29458332 (2018)). Additionally, this variant has been reported in a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Functional studies suggests that the variant is not damaging to MSH2 protein function or splicing (PMIDs: 33357406 (2021), 30998989 (2019), 16395668 (2006)). The frequency of this variant in the general population, 0.00021 (10/48082 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Benign (1 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
ClinVar reports other pathogenic variants at position 43: Y43F
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.875
0.875
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.29
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, the PVS1 rule applies only to null variants (nonsense, frameshift, canonical splice, or large deletions). The evidence for this variant shows it is a missense change (Y43C). Therefore, this criterion is not applied at any strength because it does not meet the requirement of a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PS1 applies when a different nucleotide change results in the same amino acid change previously established as pathogenic. There is no evidence of a previously established pathogenic variant encoding Y43C. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PS2 requires de novo occurrence with confirmed maternity and paternity. There are no de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well‐established functional studies showing a deleterious effect. No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires case-control or segregation data showing increased prevalence in affected individuals. No such data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PM1 applies to variants in mutational hotspots or critical functional domains. There is no evidence that Y43 lies within a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PM2_Supporting requires absence or extremely rare frequency (<1 in 50,000 alleles; <0.002%) in gnomAD v4. The observed MAF is 0.00727% (>0.002%). Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PM3 applies to recessive inheritance with detected trans configuration. Lynch syndrome (MSH2) is dominant and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes from in-frame indels or stop-loss variants. This is a missense variant without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PM5 requires a different missense change at the same residue classified as Pathogenic by this VCEP and PP3 supporting. There is no evidence of a VCEP-established pathogenic missense at Y43. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PM6 applies to presumed de novo without full confirmation. No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires segregation evidence in families. No co-segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies in genes where missense variants are a common mechanism and benign missense are rare. MSH2 has both pathogenic and benign missense variants and no evidence supports this. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows a REVEL score of 0.88, damaging predictions from PolyPhen, MetaSVM, MetaLR, and PrimateAI. Therefore, this criterion is applied at Supporting strength because multiple in silico tools concordantly predict deleterious impact.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, PP4 requires tumor MSI or IHC data consistent with Lynch syndrome. No tumor or clinical phenotype data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when reputable sources classify the variant as pathogenic without accessible evidence. ClinVar entries are conflicting (VUS, Likely Benign, Benign). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, BA1 requires a gnomAD v4 filtering allele frequency ≥0.1% (0.001). The observed MAF is 0.00727% (<0.1%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, BS1 requires a gnomAD v4 filtering allele frequency ≥0.01% and <0.1%. The observed MAF is 0.00727% (<0.01%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for MSH2, BS2 applies when the variant is observed in trans with a pathogenic allele in controls. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 requires well‐established functional studies demonstrating no damaging effect. No functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of segregation in families. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. MSH2 has pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a pathogenic variant for a dominant disorder. No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP4 applies when multiple lines of computational evidence support a benign effect. In silico tools here predict a damaging effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant in a gene is found in a patient with an alternate molecular basis. No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without evidence. ClinVar submissions are conflicting and do not meet criteria for BP6. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to silent or intronic variants beyond splice regions. This is a missense variant. Therefore, this criterion is not applied.