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MSH6c.440T>GUncertain significance
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Variant interpretation report

MSH6 c.440T>G, p.(Leu147Arg)

NM_000179.2:c.440T>G NP_000170.1:p.(Leu147Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

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 ClinGen MSH6 VCEP v2.0.0. 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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases, with a gnomAD v4.1 allele frequency of 6.20e-07 (1/1,614,050 alleles, 0 homozygotes), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

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

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

3 Uncertain significance.

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 v2.0.0, with the data and sources behind each one.

27 criteria with recorded statuses: 1 met · 14 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000179.2:c.440T>G (p.Leu147Arg) is a missense variant in exon 2 of MSH6.

This variant is extremely rare in population databases, observed in 1 of 1,614,050 alleles in gnomAD v4.1 (AF = 6.20e-07), meeting PM2_Supporting under the InSiGHT MSH6 VCEP framework.

The variant is classified as Uncertain Significance in ClinVar by 3 clinical laboratories (ClinVar Variation ID: 1740396) with no expert panel submissions.

No variant-specific functional studies, cosegregation data, de novo observations, or tumor phenotype data were identified in the VCEP functional assay documentation, ClinVar submissions, or published literature.

In silico predictors are inconclusive: HCI prior probability is 0.3529 (below PP3 thresholds), REVEL score is 0.222, BayesDel is -0.269843, and SpliceAI predicts no splicing impact (delta = 0.01). These do not meet thresholds for PP3 or BP4 under the VCEP framework.

No same-residue pathogenic comparator variant (PM5) or same-amino-acid nucleotide change comparator (PS1) was identified in the VCEP pilot variants.

With only PM2_Supporting met, and no benign or additional pathogenic criteria fulfilled, the variant is classified as Uncertain Significance under the InSiGHT MSH6 VCEP v2.0.0 combination rules.

Met · 1

PM2 SupportingThis variant is extremely rare in population databases, with a gnomAD v4.1 allele frequency of 6.20e-07 (1/1,614,050 alleles, 0 homozygotes), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF = 6.20e-07 (1/1
  • 614
  • 050 alleles
  • 0 homozygotes)
  • absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Sources
gnomad_v4 ↗

Not met · 14 · evaluated, threshold not reached

PS1 No prior VCEP classification exists for a different nucleotide change encoding the same amino acid substitution (p.Leu147Arg). The VCEP pilot variants spreadsheet does not contain this residue, and no literature source reports a different nucleotide change at codon 147 classified as Pathogenic or Likely Pathogenic. Details ▾Hide ▴
Evidence considered
  • VCEP pilot variants spreadsheet reviewed
  • no variant at codon 147 (Leu) identified with a prior P/LP classification.
Still missing
  • No same-amino-acid comparator variant classified by VCEP.
Sources
vcep_vcep_pilot_variants_mmr
PS2 No de novo occurrence data are available for this variant. PS2 under the InSiGHT MSH6 VCEP requires de novo observation points derived from confirmed paternity/maternity testing, and none have been reported. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in ClinVar
  • literature
  • or VCEP materials.
Still missing
  • No de novo observations reported.
PS3 No variant-specific functional evidence is available for NM_000179.2:c.440T>G. The VCEP functional assay documentation spreadsheet does not include this variant, OncoKB reports no reviewed functional evidence, and no published functional studies were identified in the literature. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet reviewed
  • variant not listed. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional data.
Still missing
  • No calibrated functional assay data for this variant.
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmr
PM5 No different missense change at the same amino acid residue (Leu147) has been classified by the InSiGHT VCEP as Pathogenic or Likely Pathogenic. The VCEP pilot variants spreadsheet contains no entry at this residue, and no candidate comparators were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found 0 same-residue comparator variants
  • VCEP pilot variants spreadsheet contains no variant at codon 147.
Still missing
  • No same-residue pathogenic comparator variant available.
Sources
pm5_candidatesvcep_vcep_pilot_variants_mmr
PP1 No cosegregation data are available for this variant. The InSiGHT MSH6 VCEP requires Bayes likelihood ratio calculations from pedigrees, and none have been reported. Details ▾Hide ▴
Evidence considered
  • No cosegregation data identified in ClinVar
  • literature
  • or VCEP materials.
Still missing
  • No cosegregation data available.
PP3 The HCI prior probability for this variant is 0.3529, which falls below the InSiGHT MSH6 VCEP thresholds for PP3 (Supporting: >0.68; Moderate: >0.81). Additionally, REVEL (0.222) and BayesDel (-0.269843) are not strongly pathogenic, and SpliceAI delta score is 0.01, indicating no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.3529 (below PP3_Supporting threshold of >0.68)
  • REVEL = 0.222
  • BayesDel = -0.269843
  • SpliceAI max delta = 0.01.
Sources
hci_priorrevelbayesdelspliceai ↗
PP4 No tumor-based evidence (MSI-H status, MMR protein IHC, or consistent tumor phenotype) is available for individuals carrying this variant. The InSiGHT MSH6 VCEP requires tumor MSI/IHC data meeting specific thresholds for PP4. Details ▾Hide ▴
Evidence considered
  • No MSI/IHC tumor data available in ClinVar
  • literature
  • or VCEP materials.
Still missing
  • No tumor phenotype data available for this variant.
BA1 The gnomAD v4.1 allele frequency (6.20e-07, 0.000062%) is far below the InSiGHT MSH6 VCEP BA1 Stand-Alone threshold of ≥0.0022 (0.22%). The grpmax filtering allele frequency is not available. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF = 6.20e-07
  • grpmax FAF = null
  • well below BA1 threshold of 0.0022.
Still missing
  • grpmax filtering allele frequency not available in gnomAD v4.1 for this variant.
Sources
gnomad_v4 ↗
BS1 The gnomAD v4.1 allele frequency (6.20e-07) is below the InSiGHT MSH6 VCEP BS1_Strong lower bound of ≥0.00022 (0.022%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.20e-07
  • below BS1 lower threshold of 0.00022.
Sources
gnomad_v4 ↗
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient meeting the VCEP clinical criteria (colorectal cancer after age 45 without CMMRD features) has been reported. Details ▾Hide ▴
Evidence considered
  • No trans co-occurrence data identified.
Still missing
  • No co-occurrence or phase-confirmed trans data available.
BS3 No variant-specific functional evidence supporting a benign effect is available. The variant was not found in the VCEP functional assay documentation spreadsheet, and no published functional studies demonstrating normal MSH6 function for this variant were identified. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet reviewed
  • variant not listed. OncoKB shows no variant-specific functional data.
Still missing
  • No functional assay data demonstrating normal function for this variant.
Sources
vcep_functional_assay_svi_documentation_mmroncokb ↗
BS4 No lack-of-cosegregation data are available. The InSiGHT MSH6 VCEP requires Bayes likelihood ratio calculations demonstrating absence of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No cosegregation or lack-of-cosegregation data identified.
Still missing
  • No segregation data available.
BP4 The HCI prior probability for this variant is 0.3529, which exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors (REVEL 0.222, BayesDel -0.269843, SpliceAI 0.01) do not provide strong evidence of a benign effect. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.3529 (above BP4_Supporting threshold of <0.11)
  • REVEL = 0.222
  • BayesDel = -0.269843
  • SpliceAI max delta = 0.01.
Sources
hci_priorrevelbayesdelspliceai ↗
BP5 No tumor-based evidence supporting a benign interpretation is available. The InSiGHT MSH6 VCEP requires MSS tumors, intact MMR protein expression, or BRAF V600E/MLH1 methylation data meeting specific thresholds, none of which have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No tumor MSS/IHC/BRAF/methylation data available for this variant.
Still missing
  • No tumor data available to support benign interpretation.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable. NM_000179.2:c.440T>G is a missense variant (p.Leu147Arg) and does not fall into any of the VCEP-defined PVS1 null-variant categories (nonsense, frameshift, canonical splice, initiation codon, or large genomic alteration). Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant eligible for PVS1 under the InSiGHT MSH6 VCEP PVS1 decision framework.
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPPS4 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks PS4 as Not Applicable.
Sources
cspec ↗
PM1 VCEPPM1 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks PM1 as Not Applicable.
Sources
cspec ↗
PM6 VCEPPM6 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks PM6 as Not Applicable.
Sources
cspec ↗
PP2 VCEPPP2 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks PP2 as Not Applicable.
Sources
cspec ↗
PP5 VCEPPP5 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks PP5 as Not Applicable.
Sources
cspec ↗
BP1 VCEPBP1 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks BP1 as Not Applicable.
Sources
cspec ↗
BP2 VCEPBP2 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks BP2 as Not Applicable.
Sources
cspec ↗
BP3 VCEPBP3 is a trivially skipped criterion (in-frame indels in repetitive regions); not applicable to a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP3 applies only to in-frame indels in repetitive regions.
BP6 VCEPBP6 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0); this criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee. Details ▾Hide ▴
Evidence considered
  • VCEP explicitly marks BP6 as Not Applicable per ClinGen SVI VCEP Review Committee recommendation.
Sources
cspec ↗
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. NM_000179.2:c.440T>G is a missense substitution (p.Leu147Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies only to synonymous or deep intronic variants.
PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the InSiGHT MSH6 VCEP specifications. Details ▾Hide ▴
Evidence considered
  • Standard ACMG/AMP criteria set does not include a PS5 criterion.

Identifiers

Gene
MSH6
Transcript
NM_000179.2
Coding (HGVS c.)
NM_000179.2:c.440T>G
Protein (HGVS p.)
NP_000170.1:p.(Leu147Arg)
GRCh38
chr2:47791106 T>G
GRCh37
chr2:48018245 T>G
ClinVar
1745910, 1740396

Gene diagram

Every interpreted variant in MSH6, mapped onto the exon structure of NM_000179.2. Select a row to find it on the plot.

MSH6NM_000179.2
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,614,050 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,050 alleles · 0 hom
African/African American1 / 74,926 1.3e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19559e-07; MAF= 0.00006%, 1/1614050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33465e-05; MAF= 0.00133%, 1/74926 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -243 bp
0.000
SpliceAI acceptor gainat -179 bp
0.010
SpliceAI donor lossat -14 bp
0.000
SpliceAI donor gainat +17 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
0.222
BayesDel
-0.270

How the predictions were used

PP3 The HCI prior probability for this variant is 0.3529, which falls below the InSiGHT MSH6 VCEP thresholds for PP3 (Supporting: >0.68; Moderate: >0.81). Additionally, REVEL (0.222) and BayesDel (-0.269843) are not strongly pathogenic, and SpliceAI delta score is 0.01, indicating no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.3529 (below PP3_Supporting threshold of >0.68)
  • REVEL = 0.222
  • BayesDel = -0.269843
  • SpliceAI max delta = 0.01.
Sources
hci_priorrevelbayesdelspliceai ↗
BP4 The HCI prior probability for this variant is 0.3529, which exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors (REVEL 0.222, BayesDel -0.269843, SpliceAI 0.01) do not provide strong evidence of a benign effect. Details ▾Hide ▴
Evidence considered
  • HCI prior = 0.3529 (above BP4_Supporting threshold of <0.11)
  • REVEL = 0.222
  • BayesDel = -0.269843
  • SpliceAI max delta = 0.01.
Sources
hci_priorrevelbayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. NM_000179.2:c.440T>G is a missense substitution (p.Leu147Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies only to synonymous or deep intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.222. BayesDel score = -0.269843. HCI prior probability for pathogenicity = 0.3529. MAPP score = 24.22. Custom PP2 score = 0.319.

6 paper records 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

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    This publication is the ACMG/AMP standards and guidelines for sequence variant interpretation. NM_000179.2:c.440T>G was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗
  • Lynch Syndrome.
    Adam MP et al. · 1993
    GeneReviews overview of Lynch syndrome. NM_000179.2:c.440T>G was not identified in the abstract or indexed content.
    Does not name this variant
    PMID 20301390 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    Lu KH et al. · 2014
    ASCO expert statement on cancer family history collection for oncology providers. NM_000179.2:c.440T>G was not identified in the full text.
    Does not name this variant
    PMID 24493721 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    Miller DT et al. · 2021
    ACMG SF v3.0 policy statement listing MSH6 as a secondary findings gene for Lynch syndrome. NM_000179.2:c.440T>G was not identified in the full text.
    Does not name this variant
    PMID 34012068 ↗
  • Endometrial cancer: a review and current management strategies: part I.
    SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014
    Review article on endometrial cancer management strategies. NM_000179.2:c.440T>G was not identified.
    Does not name this variant
    PMID 24905773 ↗
  • Endometrial cancer: a review and current management strategies: part II.
    SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014
    Review article on endometrial cancer management strategies (part II). NM_000179.2:c.440T>G was not identified.
    Does not name this variant
    PMID 24929052 ↗

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

gnomAD v4.1 1 / 1,614,050 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 3 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 ↗
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

This variant is present in gnomAD v4.1 (AF= 6.19559e-07; MAF= 0.00006%, 1/1614050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33465e-05; MAF= 0.00133%, 1/74926 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 1740396)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.222. BayesDel score = -0.269843. HCI prior probability for pathogenicity = 0.3529. MAPP score = 24.22. Custom PP2 score = 0.319.

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.