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MSH6c.1301A>GUncertain significance
Print report
Variant interpretation report

MSH6 c.1301A>G, p.Glu434Gly

NM_000179.3:c.1301A>G NP_000170.1:p.(Glu434Gly) Missense · exon 4 View identifiers
Classification
Uncertain significance

Variant description:

The MSH6 NM_000179.3:c.1301A>G (NP_000170.1:p.(Glu434Gly)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MSH6

MSH6 encodes a protein in the DNA mismatch repair system, which fixes errors made during DNA replication. Partnering with MSH2, it forms a complex that recognizes and helps correct mismatched DNA bases, keeping the genetic code stable. Inherited mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), raising the risk of colorectal, endometrial, ovarian, and other cancers, while mutations in both copies lead to constitutional mismatch repair deficiency. Because faulty mismatch repair drives tumor development and produces microsatellite instability, MSH6 acts as a tumor suppressor, and cancers with such repair defects often respond well to immune checkpoint inhibitor therapy.

NCBI Gene ↗ OncoKB ↗
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 ClinGen MSH6 VCEP v2.0. 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

Met at Supporting: gnomAD v4.1 reports the variant absent, satisfying the VCEP PM2 threshold of <0.00002 allele frequency.

PP3Moderate
PP3 · moderate

Met at moderate strength: HCI prior pathogenicity probability is 0.9328, exceeding the VCEP PP3_Moderate threshold of >0.81.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 (supporting) and PP3 (moderate) do not satisfy any MSH6 VCEP pathogenic or benign combination rule.

02The sources

Evidence at a glance

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

No screenshot for this evidence
REVEL score
0.960 recorded score

Recorded REVEL score: 0.960. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 →
No screenshot for this evidence
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial 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 ClinGen MSH6 VCEP v2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For the requested consequence criteria, PVS1, PM4, and BP3 are not applicable under the MSH6 VCEP rules for this missense variant.

PS2, PP1, and BS4 are not assessed because the case contains no proband de novo documentation, parental testing, pedigree segregation or non-segregation data, or Bayes Likelihood Ratios.

PM6 is not applicable because the MSH6 VCEP specification explicitly marks it as not applicable.

PS4, PP5, and BP6 are not applicable under the governing MSH6 VCEP specification. PP4 and BP5 remain not assessed because the available evidence contains no patient-level tumor or phenotype data needed by their VCEP rules.

PM3 was not assessed because the required affected-proband, partner-variant, and phase evidence is absent.

BP2 is not applicable under the MSH6 VCEP specification; no other criteria were adjudicated.

The VCEP's exact HCI prior lookup row governs PP3 and BP4 for this missense variant: 0.9328 establishes PP3_Moderate and does not meet BP4.

BP7 is outside scope because the variant is missense rather than synonymous or intronic.

Met · 2

PM2 SupportingVCEPMet at Supporting: gnomAD v4.1 reports the variant absent, satisfying the VCEP PM2 threshold of <0.00002 allele frequency. Details ▾Hide ▴
Reasoning

The governing VCEP PM2 rule assigns Supporting strength for an absent or extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in the gnomAD v4 dataset. The variant is absent from gnomAD v4.1, satisfying the VCEP's absent-allele requirement. The VCEP pilot-variants table was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching entry was found.

VCEP rule
Absent/extremely rare allele frequency \<0.00002 (\<1 in 50,000 alleles ) in gnomAD v4 dataset
Evidence considered
  • gnomAD v4.1 query for 2-47799284-A-G (GRCh38) returned search_status=absent and found=false; this is below the VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles).
  • The VCEP-pilot-variants---MMR.xlsx full-text file was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching row was found.
Still missing
  • VCEP-pilot-variants---MMR.xlsx: no entry found for c.1301A>G, p.Glu434Gly, or p.E434G.
Sources
cspec ↗gnomad_v4 ↗
PP3 ModerateVCEPMet at moderate strength: HCI prior pathogenicity probability is 0.9328, exceeding the VCEP PP3_Moderate threshold of >0.81. Details ▾Hide ▴
Reasoning

This is a missense variant, so the VCEP's HCI-prior missense pathway applies. The governing rule assigns PP3_Moderate when the HCI prior probability for pathogenicity is >0.81. The exact HCI-PRIORS-MSH6 row for c.1301A>G / p.E434G reports pathogenicity probability 0.9328, which exceeds 0.81. The HCI table's pre-assigned result therefore establishes PP3 at Moderate strength. REVEL, BayesDel, and SpliceAI were not used because they are not named by the governing PP3 pathway for this missense situation.

VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS)
Evidence considered
  • HCI-PRIORS-MSH6.txt, row MSH6_02847: c.1301A>G / p.E434G; HCI prior probability of pathogenicity = 0.9328 (MAPP score 28.23; pre-assigned PP3_Moderate because 0.9328 > 0.81).
Sources
vcep_hci_priors_msh6 ↗

Not met · 4 · evaluated, threshold not reached

PM5 VCEPNot met: the comparator search found 0 same-residue variants at Glu434, including 0 expert-panel Pathogenic/Likely Pathogenic candidates. Details ▾Hide ▴
Reasoning

The variant is missense at residue 434, but the collected comparator evidence contains zero same-residue candidates and zero expert-panel Pathogenic/Likely Pathogenic comparator candidates. Thus no different missense change at Glu434 satisfies the VCEP's required prior classification and non-splicing conditions for PM5.

VCEP rule
Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5\_Supporting if other variant is Likely Pathogenic due to a missense alteration.
Evidence considered
  • pm5_candidates.json reports residue E434, 7 total candidates seen, 0 same-residue candidates, 0 expert-panel P/LP candidates, and no useful candidates found.
  • The VCEP PM5 rule requires a different missense change at the same amino-acid residue with prior VCEP Pathogenic or Likely Pathogenic classification on the protein level and not due to aberrant splicing.
Sources
cspec ↗pm5_candidates
BA1 VCEPNot met: gnomAD v4.1 reports the variant absent, providing no Grpmax allele frequency ≥0.0022 (0.22%) required for BA1. Details ▾Hide ▴
Reasoning

The governing VCEP BA1 rule requires a gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and exclusion as a founder pathogenic variant. The variant is absent from gnomAD v4.1, so no frequency at or above 0.0022 is observed and BA1 is not met. The VCEP pilot-variants table was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching entry was found.

VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1 query for 2-47799284-A-G (GRCh38) returned search_status=absent and found=false; therefore no Grpmax filtering allele frequency ≥0.0022 (0.22%) is present.
  • The VCEP-pilot-variants---MMR.xlsx full-text file was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching row was found.
Still missing
  • VCEP-pilot-variants---MMR.xlsx: no entry found for c.1301A>G, p.Glu434Gly, or p.E434G.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 reports the variant absent, not within the BS1 Grpmax allele-frequency interval of 0.00022 to <0.0022. Details ▾Hide ▴
Reasoning

The governing VCEP BS1 rule requires a gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022-0.22%), with exclusion as a founder pathogenic variant. The variant is absent from gnomAD v4.1, so the required frequency interval is not observed and BS1 is not met. The VCEP pilot-variants table was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching entry was found.

VCEP rule
GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and \< 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1 query for 2-47799284-A-G (GRCh38) returned search_status=absent and found=false; therefore the required Grpmax filtering allele-frequency interval ≥0.00022 and <0.0022 (0.022-0.22%) is not observed.
  • The VCEP-pilot-variants---MMR.xlsx full-text file was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching row was found.
Still missing
  • VCEP-pilot-variants---MMR.xlsx: no entry found for c.1301A>G, p.Glu434Gly, or p.E434G.
Sources
cspec ↗gnomad_v4 ↗
BP4 VCEPNot met: HCI prior pathogenicity probability is 0.9328, not below the VCEP BP4 missense threshold of <0.11. Details ▾Hide ▴
Reasoning

This is a missense variant, so the missense branch of the VCEP BP4 rule is applicable. That branch requires an HCI prior probability of pathogenicity <0.11; the exact HCI-PRIORS-MSH6 row for c.1301A>G / p.E434G reports 0.9328, not <0.11. The alternative BP4 branch is restricted to intronic and synonymous variants and therefore does not apply. SpliceAI's 0.023 score was not used for BP4 because the VCEP does not name that splice pathway for missense variants.

VCEP rule
Missense variant with HCI-prior probability of pathogenicity \<0.11 as per https://hci-priors.hci.utah.edu/PRIORS OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score \<= 0.1 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH6.txt, row MSH6_02847: c.1301A>G / p.E434G; HCI prior probability of pathogenicity = 0.9328, which fails the BP4 missense cutoff of <0.11.
Sources
vcep_hci_priors_msh6 ↗

Not assessed · 10 · no assessment recorded

PS1 VCEPNot assessed: no VCEP-established pathogenic variant with a different nucleotide change encoding the same p.Glu434Gly amino-acid change was available. Details ▾Hide ▴
Reasoning

The variant is a predicted missense substitution, but the available evidence does not establish a different nucleotide change encoding p.Glu434Gly/p.E434G that this VCEP previously classified as Pathogenic, and no confirmed splice-defect route is available. The governing PS1 rule therefore cannot be applied from the evidence reviewed.

VCEP rule
A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect). OR Variants affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.
Evidence considered
  • The governing CSPEC PS1 rule requires a different underlying nucleotide change producing the same amino-acid change and prior VCEP Pathogenic classification; the case evidence contains no qualifying comparator for p.Glu434Gly/p.E434G.
Still missing
  • No VCEP-established Pathogenic comparator with a different nucleotide change encoding p.Glu434Gly/p.E434G was identified in the available evidence.
Sources
cspec ↗
PS2 VCEPNot assessed: no proband, parental-testing, de novo, tumor, or de novo-point data are available to apply the VCEP PS2 rule. Details ▾Hide ▴
Reasoning

The VCEP permits PS2 only when a proband has a de novo MSH6 variant and a Lynch syndrome spectrum tumor, with evidence weighted by confirmation of maternity and paternity and tumor MSI/IHC/methylation findings. This case evidence contains no proband, parental-testing, de novo, tumor, or de novo-point data, so no PS2 strength can be assigned.

VCEP rule
Proband with a de novo variant with both maternity and paternity confirmed in a case with MMR deficient LS spectrum tumor; or proband with a de novo variant with both maternity and paternity confirmed in a case with LS spectrum tumor without tumor data; or proband with assumed de novo variant and maternity and/or paternity unconfirmed with LS spectrum tumor.
Evidence considered
  • No case evidence documents a proband with this variant, confirmed or assumed de novo status, parental testing, or a Lynch syndrome spectrum tumor.
  • No tumor MSI/IHC/methylation results or VCEP de novo-point calculation is present.
Still missing
  • Proband-level clinical and Lynch syndrome spectrum tumor information
  • Confirmation status for maternity and paternity
  • Tumor MSI, IHC, and methylation findings where applicable
  • VCEP de novo point total
PS3 VCEPNot assessed: no variant-specific functional assay result or calibrated functional odds were available for c.1301A>G in the governing functional-assay sources. Details ▾Hide ▴
Reasoning

PS3 cannot be assessed for NM_000179.3:c.1301A>G (p.Glu434Gly/p.E434G). The governing VCEP rule requires calibrated functional evidence or a documented MMR function defect. The Functional-assay-SVI-documentation-MMR.xlsx table was searched for c.1301A>G, p.Glu434Gly, and p.E434G and contains no entry for this variant; the Functional-assay-flowchart.pdf text was likewise searched and contains no variant-specific result. The case evidence bundle reports no fetched literature PMIDs or variant-specific functional assay result. Therefore, no PS3 strength can be assigned without a variant-specific assay result, calibrated functional odds, or qualifying concordant assay evidence.

VCEP rule
Calibrated functional assays with functional odds forpathogenicity > 18.7...Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7 OR MMR function defect following functional assay flowchart* OR Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block....Calibrated functional odds for pathogenicity >2.08 and <= 4.3
Evidence considered
  • ClinGen InSiGHT MMR functional assay SVI documentation, sheet 'MMR assays': lists validated assay types, control requirements, readout thresholds, and proposed PS3/BS3 use, but has no row for c.1301A>G, p.Glu434Gly, or p.E434G.
  • ClinGen InSiGHT MMR functional assay flowchart: for an in-frame or missense variant, directs use of a calibrated functional assay or two independent concordant assays; it provides no variant-specific result for this variant.
  • The three requested variant notations were searched in both governing functional-assay full-text files; no variant-specific functional record was found.
Still missing
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in Functional-assay-flowchart.pdf.txt.
  • A variant-specific functional assay result, calibrated functional odds, or qualifying concordant assay data is unavailable.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗
PM3 VCEPNot assessed: no documented pathogenic partner variant, affected-proband CMMRD features, or phase evidence is available to assign PM3 points. Details ▾Hide ▴
Reasoning

The MSH6 VCEP PM3 rule requires co-occurrence with a known pathogenic/likely pathogenic variant in the same gene in a patient with clinical features consistent with CMMRD. A pathogenic/likely pathogenic partner variant, affected-proband observation, phase determination, and CMMRD clinical features are not documented for NM_000179.3:c.1301A>G in the available case evidence. Therefore, no PM3 points can be assigned and PM3 cannot be assessed.

VCEP rule
Co-occurrence with a known pathogenic/likely pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD as per Aronson et al 2022 - Refer to “Table for CMMRD diagnosis.pdf”. For MLH1 variants - the variant has to meet PM2\_Supporting criteria. ... Classification/zygosity of other variant: ... Pathogenic/Likely Pathogenic _in trans_: 1.0 point; ... Pathogenic/Likely Pathogenic - phase unknown: 0.5 points ... Sum all cases with the above evidence to determine the PM3 strength.
Evidence considered
  • Case evidence contains no reported affected-proband co-occurrence, pathogenic/likely pathogenic MSH6 partner variant, phase result, or CMMRD clinical-feature assessment for NM_000179.3:c.1301A>G.
  • ClinGen InSiGHT MSH6 VCEP PM3 rule: co-occurrence with a known pathogenic/likely pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD; pathogenic/likely pathogenic in trans = 1.0 point and phase unknown = 0.5 points, with points summed across cases.
Still missing
  • Documented affected proband or probands with clinical features consistent with CMMRD
  • A known pathogenic or likely pathogenic MSH6 partner variant
  • Phase testing establishing the variants in trans, or an explicit phase-unknown observation
Sources
cspec ↗
PP1 VCEPNot assessed: no pedigree segregation results or combined Bayes Likelihood Ratio are available for comparison with the VCEP thresholds. Details ▾Hide ▴
Reasoning

The VCEP requires co-segregation with disease in one or more pedigrees and a combined Bayes Likelihood Ratio to assign PP1 strength. The case evidence contains no pedigree, affected-relative testing, meioses, segregation results, or Bayes Likelihood Ratio, so PP1 cannot be assessed.

VCEP rule
Co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >18.7 in ≥2 families; >4.3 and ≤18.7; or >2.08 and ≤4.3.
Evidence considered
  • No family pedigree, affected-relative genotypes, informative meioses, or segregation analysis is documented.
  • No combined Bayes Likelihood Ratio is reported.
Still missing
  • Pedigree with disease status and variant status for informative relatives
  • Informative meioses and segregation results
  • Combined Bayes Likelihood Ratio
PP4 VCEPNot assessed: no patient tumor phenotype, MSI, tumor-genome, or MMR-protein-expression evidence is available for the PP4 rule. Details ▾Hide ▴
Reasoning

The VCEP PP4 rule requires CRC or endometrial MSI-H tumors, tumor-genome evidence, and/or loss of MMR protein expression consistent with the variant location. The available case evidence contains no patient phenotype, tumor MSI, tumor-genome, or MMR-protein-expression findings, so PP4 cannot be assessed. The on-record Table-for-CMMRD-diagnosis.pdf and VCEP-pilot-variants---MMR.xlsx were searched for c.1301A>G, p.Glu434Gly, and p.E434G; neither contains an entry for this variant.

Evidence considered
  • The VCEP PP4 rule requires 1, 2, or at least 3 independent CRC/endometrial MSI-H tumors, tumor-genome evidence, and/or loss of MMR protein expression consistent with the variant location, depending on strength.
  • The case bundle provides no patient-level tumor or phenotype findings for this variant.
  • Table-for-CMMRD-diagnosis.pdf was searched for c.1301A>G, p.Glu434Gly, and p.E434Gly; no matching variant entry was found.
  • VCEP-pilot-variants---MMR.xlsx was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching variant entry was found.
Still missing
  • Patient-level phenotype and tumor evidence are unavailable for PP4 evaluation.
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in Table-for-CMMRD-diagnosis.pdf.
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in VCEP-pilot-variants---MMR.xlsx.
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis ↗vcep_vcep_pilot_variants_mmr ↗
BS2 VCEPNot assessed: no documented in-trans co-occurrence, qualifying patient age, CMMRD assessment, or parental/offspring phase confirmation is available. Details ▾Hide ▴
Reasoning

The governing VCEP BS2 rule requires co-occurrence in trans with a known pathogenic sequence variant in the same gene in an appropriately aged cancer patient without CMMRD manifestations, with phase confirmation by parental or offspring testing. The available evidence contains no such co-occurrence, phase, age, or CMMRD assessment for this variant. The VCEP pilot-variants table was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching entry was found.

VCEP rule
Co-occurrence _​in trans_ with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS<sup>​d​</sup>), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.
Evidence considered
  • No case evidence documents co-occurrence in trans with a known pathogenic MSH6 sequence variant, a qualifying colorectal or other Lynch syndrome cancer age, absence of CMMRD manifestations, or phase confirmation by testing parents or offspring.
  • The VCEP-pilot-variants---MMR.xlsx full-text file was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching row was found.
Still missing
  • No qualifying in-trans co-occurrence and phase-confirmation evidence was available.
  • VCEP-pilot-variants---MMR.xlsx: no entry found for c.1301A>G, p.Glu434Gly, or p.E434G.
Sources
cspec ↗
BS3 VCEPNot assessed: no variant-specific proficient-function assay result or calibrated functional odds were available for c.1301A>G in the governing functional-assay sources. Details ▾Hide ▴
Reasoning

BS3 cannot be assessed for NM_000179.3:c.1301A>G (p.Glu434Gly/p.E434G). The governing VCEP rule requires calibrated functional odds or variant-specific proficient function demonstrated by protein and mRNA-based assays under the MMR functional assay flowchart. The Functional-assay-SVI-documentation-MMR.xlsx table was searched for c.1301A>G, p.Glu434Gly, and p.E434G and contains no entry for this variant; the Functional-assay-flowchart.pdf text was likewise searched and contains no variant-specific result. The case evidence bundle reports no fetched literature PMIDs or variant-specific functional assay result. Therefore, neither BS3_Strong nor BS3_Supporting can be assigned.

VCEP rule
Calibrated functional assays with functional odds for Pathogenicity <= 0.05 OR Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations....Calibrated functional assays with functional odds for Pathogenicity >0.05 & <=0.48 OR Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.
Evidence considered
  • ClinGen InSiGHT MMR functional assay SVI documentation, sheet 'MMR assays': lists validated assay types, control requirements, readout thresholds, and proposed PS3/BS3 use, but has no row for c.1301A>G, p.Glu434Gly, or p.E434G.
  • ClinGen InSiGHT MMR functional assay flowchart: defines proficient-function paths for qualifying assay results, but provides no variant-specific result for this variant.
  • The three requested variant notations were searched in both governing functional-assay full-text files; no variant-specific functional record was found.
Still missing
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in Functional-assay-SVI-documentation-MMR.xlsx.txt.
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in Functional-assay-flowchart.pdf.txt.
  • A variant-specific proficient-function assay result, calibrated functional odds, or qualifying protein and mRNA assay data is unavailable.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmr ↗vcep_functional_assay_flowchart ↗
BS4 VCEPNot assessed: no non-segregation pedigree data or combined Bayes Likelihood Ratio are available for comparison with the VCEP thresholds. Details ▾Hide ▴
Reasoning

The VCEP requires lack of co-segregation in pedigree(s) quantified by a combined Bayes Likelihood Ratio below the specified threshold. The case evidence contains no pedigree, non-segregating affected relatives, or Bayes Likelihood Ratio, so BS4 cannot be assessed.

VCEP rule
Lack of co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio <0.05 for Strong, or >0.05 and ≤0.48 for Supporting.
Evidence considered
  • No pedigree, affected-relative non-segregation results, or segregation analysis is documented.
  • No combined Bayes Likelihood Ratio is reported.
Still missing
  • Pedigree with disease status and variant status for informative relatives
  • Documented non-segregation observations
  • Combined Bayes Likelihood Ratio
BP5 VCEPNot assessed: no tumor MSS, MMR-protein, BRAF V600E, or MLH1-methylation evidence is available for BP5. Details ▾Hide ▴
Reasoning

The VCEP BP5 rule requires either at least 2 or at least 4 tumors with MSS and/or no loss of MMR protein expression and/or inconsistent LS-spectrum MMR loss, or BRAF V600E/MLH1 methylation evidence. No patient-level tumor, MSI, MMR-protein, BRAF, or MLH1-methylation evidence is available, so BP5 cannot be assessed.

Evidence considered
  • The VCEP BP5 Strong rule requires at least 4 qualifying tumors or at least 2 BRAF V600E/MLH1-methylation findings.
  • The VCEP BP5 Supporting rule requires 2 or 3 qualifying tumors or 1 BRAF V600E/MLH1-methylation finding.
  • The case bundle contains no patient-level tumor or molecular phenotype findings for this variant.
Still missing
  • Patient-level tumor and molecular phenotype evidence are unavailable for BP5 evaluation.
Sources
cspec ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1301A>G is a missense substitution, not a VCEP-specified nonsense, frameshift, splice-site, genomic-alteration, or qualifying RNA-aberration variant. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. The variant is NM_000179.3:c.1301A>G, NP_000170.1:p.(Glu434Gly), a missense substitution in exon 4; it does not introduce a premature termination codon, large genomic alteration, canonical splice-site alteration, or a patient-RNA-confirmed splicing aberration leading to truncation or a qualifying in-frame deletion. The governing MSH6 PVS1 rule names nonsense/frameshift PTCs, large genomic alterations, specified splice-site variants, and qualifying patient-RNA splicing aberrations, so no PVS1 strength tier applies. The required VCEP reference files PVS1_DecisionTree_MMR.pdf and VCEP-pilot-variants---MMR.xlsx were searched for c.1301A>G, p.Glu434Gly, and p.E434G; neither file contains an entry for this variant.

VCEP rule
Nonsense/frameshift variant introducing Premature Termination Codon (PTC)<sup>a</sup> ≤ codon 1341 in _MSH6_. Refer to Appendix for details.
Evidence considered
  • Case normalization identifies NM_000179.3:c.1301A>G as NP_000170.1:p.(Glu434Gly) / p.(E434G), a missense variant in exon 4.
  • The VCEP PVS1 rule applies to nonsense/frameshift PTCs, large genomic alterations, specified splice-site variants, and qualifying patient-RNA-confirmed splicing aberrations; none describes this missense variant.
  • Searched PVS1_DecisionTree_MMR.pdf.txt and VCEP-pilot-variants---MMR.xlsx.txt for c.1301A>G, p.Glu434Gly, and p.E434G; no matching entry was found.
Still missing
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in PVS1_DecisionTree_MMR.pdf.txt.
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in VCEP-pilot-variants---MMR.xlsx.txt.
Sources
cspec ↗vcep_pvs1_decisiontree_mmr ↗vcep_vcep_pilot_variants_mmr ↗
PS4 VCEPNot applicable: the MSH6 VCEP specification explicitly marks PS4 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing MSH6 VCEP specification marks PS4 as Not Applicable; therefore no case-control enrichment calculation is performed.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT MSH6 VCEP specification v2.0 lists PS4 applicability as Not Applicable.
Sources
cspec ↗
PM1 VCEPNot applicable: the MSH6 VCEP marks PM1 Not Applicable, regardless of p.E434G's location in the functional-domain schematic. Details ▾Hide ▴
Reasoning

The MSH6 CSPEC marks PM1 Not Applicable. The governing MSH6 functional-domain file was searched for c.1301A>G, p.Glu434Gly, and p.E434G; it contains no variant-specific entry, and the authoritative vcep_materials.json domain_tables object is empty. No PM1 evidence can therefore be assigned under this VCEP specification.

VCEP rule
Not Applicable
Evidence considered
  • The CSPEC PM1 entry states Not Applicable and specifies that there are no recognized mutational hot spots usable for classification purposes.
  • MMR-Functional-domains.pdf.txt was searched for c.1301A>G, p.Glu434Gly, and p.E434G; no matching variant row was found.
Still missing
  • No entry for c.1301A>G, p.Glu434Gly, or p.E434G was found in MMR-Functional-domains.pdf.txt; PM1 remains not applicable under the CSPEC rule.
Sources
cspec ↗vcep_mmr_functional_domains ↗
PM4 VCEPNot applicable: the MSH6 VCEP specification explicitly marks PM4 Not Applicable. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the MSH6 VCEP specification, which explicitly designates this criterion as Not Applicable. No PM4 evidence is therefore assessed for this missense variant.

VCEP rule
Not Applicable
Evidence considered
  • The MSH6 Version 2.0 CSPEC entry for PM4 states applicability: Not Applicable.
Sources
cspec ↗
PM6 VCEPNot applicable: the MSH6 VCEP explicitly marks PM6 as not applicable for this specification. Details ▾Hide ▴
Reasoning

The MSH6 VCEP explicitly marks PM6 as not applicable; therefore assumed de novo evidence without confirmed maternity and/or paternity cannot be assigned under this criterion.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT MSH6 specification v2.0, PM6 entry: applicability is "Not Applicable".
Sources
cspec ↗
PP2 VCEPNot applicable: the MSH6 VCEP explicitly marks PP2 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The MSH6 CSPEC marks PP2 Not Applicable; no generic gene-level missense mechanism or benign-missense-rate rule may substitute for that VCEP applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • The MSH6 CSPEC PP2 entry states Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the MSH6 VCEP specification explicitly marks PP5 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing MSH6 VCEP specification marks PP5 as Not Applicable; no third-party classification is used for PP5.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT MSH6 VCEP specification v2.0 lists PP5 applicability as Not Applicable.
Sources
cspec ↗
BP1 VCEPNot applicable: the MSH6 VCEP explicitly marks BP1 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The MSH6 CSPEC marks BP1 Not Applicable; no generic benign-missense mechanism rule may substitute for that VCEP applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • The MSH6 CSPEC BP1 entry states Not Applicable.
Sources
cspec ↗
BP2 VCEPNot applicable: the MSH6 VCEP explicitly excludes BP2 and directs evaluators to use BS2 instead. Details ▾Hide ▴
Reasoning

The MSH6 VCEP marks BP2 as not applicable and directs that BS2 is used instead. BP2 is therefore not evaluated, regardless of whether any cis or trans observation is available.

VCEP rule
BS2 is used instead.
Evidence considered
  • ClinGen InSiGHT MSH6 VCEP criterion entry for BP2 states: “BP2 is not applicable” and “BS2 is used instead.”
Sources
cspec ↗
BP3 VCEPNot applicable: the MSH6 VCEP specification explicitly marks BP3 Not Applicable. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the MSH6 VCEP specification, which explicitly designates this criterion as Not Applicable. No BP3 evidence is therefore assessed for this missense variant.

VCEP rule
Not Applicable
Evidence considered
  • The MSH6 Version 2.0 CSPEC entry for BP3 states applicability: Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the MSH6 VCEP specification explicitly marks BP6 as Not Applicable. Details ▾Hide ▴
Reasoning

The governing MSH6 VCEP specification marks BP6 as Not Applicable; no benign source assertion is used for BP6.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT MSH6 VCEP specification v2.0 lists BP6 applicability as Not Applicable.
Sources
cspec ↗
BP7 N/ANot applicable: the variant is missense, whereas the VCEP BP7 rule covers only synonymous or intronic variants at or beyond -21/+7. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous (silent) or intronic variants at or beyond -21/+7 of the exonic boundary. This variant is missense (c.1301A>G, p.Glu434Gly) and is outside BP7's stated scope, so BP7 is not applicable.

VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Case normalization identifies NM_000179.3:c.1301A>G as the missense substitution NP_000170.1:p.(Glu434Gly).

Identifiers

Gene
MSH6
Transcript
NM_000179.3
Coding (HGVS c.)
NM_000179.3:c.1301A>G
Protein (HGVS p.)
NP_000170.1:p.(Glu434Gly)
GRCh38
chr2:47799284 A>G
GRCh37
chr2:48026423 A>G
Location and type
Exon 4 · missense

Gene diagram

Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.3. Select a row to find it on the plot.

MSH6NM_000179.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -16 bp
0.000
SpliceAI acceptor gainat +111 bp
0.001
SpliceAI donor lossat +305 bp
0.016
SpliceAI donor gainat -17 bp
0.023
Pangolin splice lossmagnitude shown
-0.023
Pangolin splice gain
0.024

Other predictors

REVEL
0.960
BayesDel
0.478

How the predictions were used

PP3 ModerateVCEPMet at moderate strength: HCI prior pathogenicity probability is 0.9328, exceeding the VCEP PP3_Moderate threshold of >0.81. Details ▾Hide ▴
Reasoning

This is a missense variant, so the VCEP's HCI-prior missense pathway applies. The governing rule assigns PP3_Moderate when the HCI prior probability for pathogenicity is >0.81. The exact HCI-PRIORS-MSH6 row for c.1301A>G / p.E434G reports pathogenicity probability 0.9328, which exceeds 0.81. The HCI table's pre-assigned result therefore establishes PP3 at Moderate strength. REVEL, BayesDel, and SpliceAI were not used because they are not named by the governing PP3 pathway for this missense situation.

VCEP rule
Missense variant with HCI prior probability for pathogenicity >0.81 as per [https://hci-priors.hci.utah.edu/PRIORS](https://hci-priors.hci.utah.edu/PRIORS)
Evidence considered
  • HCI-PRIORS-MSH6.txt, row MSH6_02847: c.1301A>G / p.E434G; HCI prior probability of pathogenicity = 0.9328 (MAPP score 28.23; pre-assigned PP3_Moderate because 0.9328 > 0.81).
Sources
vcep_hci_priors_msh6 ↗
BP4 VCEPNot met: HCI prior pathogenicity probability is 0.9328, not below the VCEP BP4 missense threshold of <0.11. Details ▾Hide ▴
Reasoning

This is a missense variant, so the missense branch of the VCEP BP4 rule is applicable. That branch requires an HCI prior probability of pathogenicity <0.11; the exact HCI-PRIORS-MSH6 row for c.1301A>G / p.E434G reports 0.9328, not <0.11. The alternative BP4 branch is restricted to intronic and synonymous variants and therefore does not apply. SpliceAI's 0.023 score was not used for BP4 because the VCEP does not name that splice pathway for missense variants.

VCEP rule
Missense variant with HCI-prior probability of pathogenicity \<0.11 as per https://hci-priors.hci.utah.edu/PRIORS OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score \<= 0.1 as per Walker et al 2023.
Evidence considered
  • HCI-PRIORS-MSH6.txt, row MSH6_02847: c.1301A>G / p.E434G; HCI prior probability of pathogenicity = 0.9328, which fails the BP4 missense cutoff of <0.11.
Sources
vcep_hci_priors_msh6 ↗
BP7 N/ANot applicable: the variant is missense, whereas the VCEP BP7 rule covers only synonymous or intronic variants at or beyond -21/+7. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous (silent) or intronic variants at or beyond -21/+7 of the exonic boundary. This variant is missense (c.1301A>G, p.Glu434Gly) and is outside BP7's stated scope, so BP7 is not applicable.

VCEP rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Case normalization identifies NM_000179.3:c.1301A>G as the missense substitution NP_000170.1:p.(Glu434Gly).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.96. BayesDel score = 0.477967. HCI prior probability for pathogenicity = 0.9328. MAPP score = 28.23. Custom PP2 score = 0.997.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.023 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 ↗
ClinGen CSpec Captured ClinGen CSpec 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.96. BayesDel score = 0.477967. HCI prior probability for pathogenicity = 0.9328. MAPP score = 28.23. Custom PP2 score = 0.997.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial 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.