0%
MSH3c.8G>ALikely benign
Print report
Variant interpretation report

MSH3 c.8G>A, p.(Arg3His)

NM_002439.5:c.8G>A NP_002430.3:p.(Arg3His) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MSH3

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is extremely rare in large population databases: gnomAD v2.1 AF=4.32×10⁻⁶ (1/231,498 alleles), gnomAD v4.1 AF=3.13×10⁻⁶ (5/1,599,926 alleles), grpmax FAF=1.25×10⁻⁶, and absent from gnomAD-Canada. All observed allele frequencies are well below the 0.1% PM2 threshold. No homozygous individuals have been observed. One ClinVar submitter (Labcorp/Invitae) noted potential data quality concerns at this position in gnomAD but did not provide alternative frequency data.

Benign criteria applied · 2
BP1Supporting
BP1 · supporting

This is a missense variant (p.Arg3His) in MSH3, a gene for which the established disease mechanism is primarily biallelic loss-of-function via truncating variants. MSH3-related autosomal recessive adenomatous polyposis is caused by biallelic LoF variants. A missense variant in a gene where primarily truncating variants are known to cause disease meets BP1.

BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.31 (below pathogenic threshold of 0.5). BayesDel score is -0.0159 (not damaging). SpliceAI predicts no splicing impact (max delta 0.00). The concordant benign predictions from multiple algorithm types support BP4.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP1 supporting benign, BP4 supporting benign; combination = 1 moderate + 2 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
5 / 1,599,926 alleles

gnomAD v4.1: 5 / 1,599,926 alleles. Recorded AF 3.12514e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.31969e-06; MAF= 0.00043%, 1/231498 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.02737e-05; MAF= 0.00303%, 1/33032 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH3, a DNA mismatch repair protein, is frequently mutated in colorectal cancers.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 19 not met · 2 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002439.5:c.8G>A (p.Arg3His) in MSH3 is a missense variant in exon 1. This variant is extremely rare in population databases (gnomAD v4.1 AF=3.13×10⁻⁶, 5/1,599,926 alleles; gnomAD v2.1 AF=4.32×10⁻⁶, 1/231,498 alleles; 0 homozygotes observed).

The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (ClinVar ID: 969087). No expert panel classification is available. The ClinVar-associated references (PMID:25394175, a cancer referral practice guideline, and PMID:28492532, the Sherloc classification framework paper) do not provide variant-specific evidence for NM_002439.5:c.8G>A.

Computational predictors do not support a deleterious effect: REVEL score 0.31 (below pathogenic threshold), BayesDel score -0.0159 (not damaging), and SpliceAI max delta 0.00 (no splicing impact predicted).

No functional studies, segregation data, de novo reports, or case-control observations have been published for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.

Evidence weighting: one moderate pathogenic criterion (PM2 — extremely low population frequency) and two supporting benign criteria (BP1 — missense in a primarily loss-of-function disease gene; BP4 — multiple concordant benign computational predictions). The net evidence is insufficient to classify this variant as pathogenic or benign, consistent with a variant of uncertain significance.

Met · 3

PM2 ModerateThis variant is extremely rare in large population databases: gnomAD v2.1 AF=4.32×10⁻⁶ (1/231,498 alleles), gnomAD v4.1 AF=3.13×10⁻⁶ (5/1,599,926 alleles), grpmax FAF=1.25×10⁻⁶, and absent from gnomAD-Canada. All observed allele frequencies are well below the 0.1% PM2 threshold. No homozygous individuals have been observed. One ClinVar submitter (Labcorp/Invitae) noted potential data quality concerns at this position in gnomAD but did not provide alternative frequency data. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/231
  • 498 (AF=0.00043%). gnomAD v4.1: 5/1
  • 599
  • 926 (AF=0.00031%). gnomAD-Canada: absent. Homozygotes: 0 in all databases. All frequencies well below PM2 <0.1% threshold.
Still missing
  • One submitter notes potential data quality concerns at this gnomAD position
  • independent confirmation of frequency data may be warranted.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 SupportingThis is a missense variant (p.Arg3His) in MSH3, a gene for which the established disease mechanism is primarily biallelic loss-of-function via truncating variants. MSH3-related autosomal recessive adenomatous polyposis is caused by biallelic LoF variants. A missense variant in a gene where primarily truncating variants are known to cause disease meets BP1. Details ▾Hide ▴
Evidence considered
  • MSH3 disease mechanism: biallelic loss-of-function. PVS1 gene context confirms LoF mechanism supported. Missense variants are not the primary disease mechanism.
Sources
pvs1_gene_context
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.31 (below pathogenic threshold of 0.5). BayesDel score is -0.0159 (not damaging). SpliceAI predicts no splicing impact (max delta 0.00). The concordant benign predictions from multiple algorithm types support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.31 (benign range). BayesDel: -0.0159 (not damaging). SpliceAI: max delta 0.00 (no splice alteration). Multiple concordant benign predictions.
Still missing
  • HCI prior not available for MSH3 gene.
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS2 No de novo occurrence has been reported for this variant in any publication or database. No parentage-confirmed de novo observation is available. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in ClinVar
  • publications
  • or supporting databases.
Still missing
  • No de novo testing or family studies available.
PS3 No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. In silico predictors (REVEL 0.31, BayesDel -0.016) do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies curated. REVEL score 0.31 (below 0.5 threshold). BayesDel score -0.0159 (not damaging).
Still missing
  • No functional studies (in vitro or in vivo) have been performed on this variant.
Sources
oncokb ↗revelbayesdel
PS4 The variant has not been observed in multiple unrelated probands with the same phenotype in peer-reviewed literature. ClinVar submissions (2 clinical laboratories) classify this variant as Uncertain significance, and the single ClinVar-associated reference (PMID:25394175) is a practice guideline that does not mention MSH3 or this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS (2 clinical labs). No case reports or cohort studies identifying this variant in affected probands. PMID:25394175 does not mention MSH3 or NM_002439.5:c.8G>A.
Still missing
  • No published case observations of this variant in disease cohorts.
Sources
clinvar ↗
PM1 The variant (p.Arg3His) is located at the extreme N-terminus of MSH3 (position 3 of 1137 amino acids), far from the conserved MutS domain that mediates DNA mismatch recognition. This residue is not within a known functional domain or a statistically significant mutational hotspot. Cancer Hotspots analysis confirms no significant clustering at this position. Details ▾Hide ▴
Evidence considered
  • Variant at amino acid position 3
  • outside MutS functional domains. Cancer Hotspots: residue not significant. No pathogenic variant clustering at this position.
PM6 No de novo occurrence of this variant has been reported in any publication or ClinVar submission. No parentage-confirmed data available. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No de novo testing data available.
PP1 No co-segregation data are available for this variant. No family studies or segregation analyses have been reported in the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No segregation or family studies identified.
Still missing
  • No family studies or segregation data available.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. MSH3-related disease (autosomal recessive adenomatous polyposis) is primarily caused by biallelic loss-of-function variants. Missense variants are not the established predominant disease mechanism, and the gene does not meet PP2 criteria. Details ▾Hide ▴
Evidence considered
  • MSH3 disease mechanism is primarily loss-of-function
  • not missense. PP2 criteria not satisfied.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score 0.31 (below pathogenic threshold of 0.5). BayesDel score -0.0159 (not damaging). SpliceAI max delta 0.00 (no splicing impact predicted). HCI prior not available for this gene. The computational evidence does not reach the threshold for PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.31 (not pathogenic). BayesDel: -0.0159 (not damaging). SpliceAI: max delta 0.00 (no splice impact). HCI prior: gene not supported.
Still missing
  • No gene-specific in silico prior (HCI) available for MSH3.
Sources
revelbayesdelspliceai ↗
PP4 No specific phenotypic or clinical data are available for individuals carrying this variant. The variant has been observed in clinical testing laboratories reporting VUS classification, but no detailed phenotype information is provided. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available for review. ClinVar submissions lack detailed clinical descriptions.
Still missing
  • No phenotype data available for carriers of this variant.
PP5 The variant is classified as Uncertain significance in ClinVar (2 clinical laboratories), not as pathogenic or likely pathogenic from a reputable source. The ClinVar-associated references (PMID:25394175, PMID:28492532) do not provide variant-specific evidence: PMID:25394175 is a cancer referral practice guideline that does not mention MSH3, and PMID:28492532 is a classification refinement methodology paper (Sherloc) that does not discuss this specific variant. No expert panel classification is available. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS (not P/LP). PMID:25394175 confirmed not to mention MSH3 or NM_002439.5:c.8G>A by full-text review.
Still missing
  • No reputable source classifies this variant as pathogenic.
Sources
clinvar ↗
BA1 The variant is extremely rare in population databases, not common. The highest observed allele frequency is 0.00043% (gnomAD v4.1 NFE), far below the 1% BA1 threshold. The variant does not meet the stand-alone benign criterion for common population variants. Details ▾Hide ▴
Evidence considered
  • Maximum AF: 0.00043% (gnomAD v4.1 NFE). Well below BA1 >1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant allele frequency is far below the 0.3% BS1 threshold. Highest subpopulation AF is 0.0073% (gnomAD v2.1 AMR_XY) and overall maximum AF is 0.00043% (gnomAD v4.1 NFE). The variant is too rare to apply BS1. Details ▾Hide ▴
Evidence considered
  • Maximum AF in any subpopulation: 0.0073% (v2.1 AMR_XY). Well below BS1 >0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No homozygous individuals have been observed in gnomAD (v2.1 or v4.1). No observation in trans with a pathogenic variant has been reported. BS2 requires observation in a healthy adult homozygous state or in trans with a pathogenic variant for a fully penetrant disorder — this evidence is absent. Details ▾Hide ▴
Evidence considered
  • Homozygotes: 0 in gnomAD v2.1 and v4.1. No trans observations reported.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. While in silico predictors are not damaging, BS3 requires direct experimental evidence showing normal function, which has not been reported. Details ▾Hide ▴
Evidence considered
  • No functional studies (in vitro or in vivo) have been performed on this variant. In silico predictions alone are insufficient for BS3.
Still missing
  • No experimental functional studies available.
BS4 No non-segregation data are available. No family studies have been reported that would demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation studies or family data available.
Still missing
  • No family-based segregation analysis performed.
BP2 No observation of this variant in trans with a known pathogenic variant in MSH3 has been reported. No data support BP2 application. Details ▾Hide ▴
Evidence considered
  • No trans observations reported in any database or publication.
Still missing
  • No phase information or trans configuration data available.
BP6 ClinVar classification for this variant is Uncertain significance, not Benign or Likely benign. Two clinical laboratories have submitted VUS classifications. BP6 requires a reputable source to classify the variant as benign/likely benign, which is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (2 labs). No benign/likely benign classification from any source.
Sources
clinvar ↗
BP7 BP7 applies to synonymous variants predicted to have no impact on splicing. This variant (c.8G>A, p.Arg3His) is a missense variant, not synonymous. BP7 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Arg3His)
  • not a synonymous variant. BP7 not applicable.
PS5 No reputable source has classified this variant as pathogenic. The ClinVar classification is Uncertain significance from two single-submitter clinical laboratories, and no expert panel review is available. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (criteria provided
  • single submitter)
  • 2 clinical laboratories. No expert panel classification.
Still missing
  • No expert panel or multi-submitter pathogenic classification.
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PS1 No evidence of a different nucleotide change at the same position (c.8) leading to the same amino acid change (p.Arg3His) has been identified in ClinVar, COSMIC, or the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No alternate nucleotide change at c.8 producing p.Arg3His identified.
Still missing
  • No comparator nucleotide change at this position available for assessment.
BP5 No clinical data are available to determine whether an alternative molecular basis for disease has been identified in any proband carrying this variant. Assessment of BP5 requires case-level clinical context not provided in the available evidence. Details ▾Hide ▴
Evidence considered
  • Insufficient clinical context to assess whether an alternative cause has been identified.
Still missing
  • Requires clinical data from the proband to determine if an alternative molecular diagnosis exists.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.8G>A, p.Arg3His) in exon 1 of MSH3. It does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). The generic PVS1 framework is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
  • Missense substitution in exon 1
  • not a null variant (nonsense
  • frameshift
  • or canonical splice site). PVS1 decision algorithm returns 'not applicable' for this variant bucket.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders; MSH3 is not established as a recessive disease gene requiring biallelic variant assessment per standard ACMG/AMP criteria. Details ▾Hide ▴
Evidence considered
  • Not assessed in a recessive disorder context.
PM4 N/APM4 applies to in-frame insertions/deletions or stop-loss variants; this is a missense substitution variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not an in-frame indel or stop-loss variant.
PM5 N/ANo same-residue pathogenic comparator variants identified at amino acid position 3. Automated PM5 candidate harvesting returned no candidates. Unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates. No ClinVar P/LP variants at Arg3 identified.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not an in-frame indel in a repetitive region.

Identifiers

Gene
MSH3
Transcript
NM_002439.5
Coding (HGVS c.)
NM_002439.5:c.8G>A
Protein (HGVS p.)
NP_002430.3:p.(Arg3His)
GRCh38
chr5:80654735 G>A
GRCh37
chr5:79950554 G>A
ClinVar
969087

Gene diagram

Every interpreted variant in MSH3, mapped onto the exon structure of NM_002439.5. Select a row to find it on the plot.

MSH3NM_002439.5
Fetching transcript structure from UCSC…
gnomAD v4.1 5 / 1,599,926 alleles AF 3.13e-06 · 0 homozygotes · FAF 1.25e-06
gnomAD v2.1 1 / 231,498 alleles AF 4.32e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,599,926 alleles · 0 hom · FAF 1.3e-06
European (non-Finnish)5 / 1,175,206 4.3e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4.3e-06 · 1 / 231,498 alleles · 0 hom
Admixed American1 / 33,032 3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.12514e-06; MAF= 0.00031%, 5/1599926 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.25457e-06; MAF= 0.00043%, 5/1175206 alleles, homozygotes = 0); grpmax FAF= 1.25e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.31969e-06; MAF= 0.00043%, 1/231498 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.02737e-05; MAF= 0.00303%, 1/33032 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.310
BayesDel
-0.016

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.31 (below pathogenic threshold of 0.5). BayesDel score is -0.0159 (not damaging). SpliceAI predicts no splicing impact (max delta 0.00). The concordant benign predictions from multiple algorithm types support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.31 (benign range). BayesDel: -0.0159 (not damaging). SpliceAI: max delta 0.00 (no splice alteration). Multiple concordant benign predictions.
Still missing
  • HCI prior not available for MSH3 gene.
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score 0.31 (below pathogenic threshold of 0.5). BayesDel score -0.0159 (not damaging). SpliceAI max delta 0.00 (no splicing impact predicted). HCI prior not available for this gene. The computational evidence does not reach the threshold for PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.31 (not pathogenic). BayesDel: -0.0159 (not damaging). SpliceAI: max delta 0.00 (no splice impact). HCI prior: gene not supported.
Still missing
  • No gene-specific in silico prior (HCI) available for MSH3.
Sources
revelbayesdelspliceai ↗
BP7 BP7 applies to synonymous variants predicted to have no impact on splicing. This variant (c.8G>A, p.Arg3His) is a missense variant, not synonymous. BP7 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Arg3His)
  • not a synonymous variant. BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.31. BayesDel score = -0.015906.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    Practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. Covers hereditary cancer syndromes including Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) but does not mention MSH3. The variant NM_002439.5:c.8G>A was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,599,926 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.12514e-06; MAF= 0.00031%, 5/1599926 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.25457e-06; MAF= 0.00043%, 5/1175206 alleles, homozygotes = 0); grpmax FAF= 1.25e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.31969e-06; MAF= 0.00043%, 1/231498 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.02737e-05; MAF= 0.00303%, 1/33032 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 969087)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.31. BayesDel score = -0.015906.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH3, a DNA mismatch repair protein, is frequently mutated in colorectal cancers.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.