0%
MSH6c.3603C>ALikely benign
Print report
Variant interpretation report

MSH6 c.3603C>A, p.(Leu1201=)

NM_000179.3:c.3603C>A NP_000170.1:p.(Leu1201=) 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 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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000179.3:c.3603C>A is extremely rare in population databases. In gnomAD v4.1 it is observed in 1 of 1,613,414 alleles (AF = 6.2 × 10⁻⁷), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Under the InSiGHT MSH6 VCEP v2.0.0 BP4 rule, synonymous variants with SpliceAI delta ≤0.1 meet BP4_Supporting.

BP7Supporting
BP7 · supporting

NM_000179.3:c.3603C>A is a synonymous (silent) variant (p.Leu1201=). Under the InSiGHT MSH6 VCEP v2.0.0, synonymous variants meet BP7_Supporting. SpliceAI predicts no splicing impact (max delta = 0.00), supporting that this variant does not alter splicing.

Recorded classification: Likely benign

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: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; 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.

SpliceAI score
0.000 maximum delta

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

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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: 3 met · 3 not met · 8 not assessed · 13 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_000179.3:c.3603C>A (p.Leu1201=) is a synonymous variant in MSH6 exon 7. SpliceAI predicts no splicing impact (delta = 0.00). The variant is extremely rare in gnomAD v4.1 (1/1,613,414 alleles; AF = 6.2 × 10⁻⁷) and absent from gnomAD v2.1, gnomAD-Canada, ClinVar, and COSMIC.

Under the InSiGHT MSH6 VCEP v2.0.0: BP7_Supporting is met because this is a synonymous variant. BP4_Supporting is met because SpliceAI delta (0.00) ≤ 0.1. PM2_Supporting is met because the variant allele frequency (6.2 × 10⁻⁷) is below the VCEP threshold of <0.00002.

Per the InSiGHT VCEP combining rules, two Benign Supporting criteria (BP4_Supporting + BP7_Supporting) with one Pathogenic Supporting criterion (PM2_Supporting) results in Uncertain Significance (VUS) — Rule31 (≥1 Benign.Supporting + ≥1 Pathogenic.Supporting → VUS Conflicting) takes precedence over Rule19 (≥2 Benign.Supporting → Likely Benign).

PVS1, PS1, PM5, PS4, PP2, PP5, PM1, PM6, BP1, BP2, BP3, BP6 are not applicable. PS2, PS3, PP1, PP4, BS2, BS3, BS4, BP5 are not assessed due to absence of de novo, functional, tumor phenotype, co-segregation, or co-occurrence data.

Met · 3

PM2 SupportingNM_000179.3:c.3603C>A is extremely rare in population databases. In gnomAD v4.1 it is observed in 1 of 1,613,414 alleles (AF = 6.2 × 10⁻⁷), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/1
  • 613
  • 414 alleles (AF = 6.2 × 10⁻⁷)
  • highest in NFE (1/1
  • 179
  • 594)
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent
Sources
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Under the InSiGHT MSH6 VCEP v2.0.0 BP4 rule, synonymous variants with SpliceAI delta ≤0.1 meet BP4_Supporting. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu1201=)
  • SpliceAI max delta = 0.00 (≤0.1 threshold for BP4_Supporting)
Sources
spliceai ↗cspec ↗
BP7 SupportingNM_000179.3:c.3603C>A is a synonymous (silent) variant (p.Leu1201=). Under the InSiGHT MSH6 VCEP v2.0.0, synonymous variants meet BP7_Supporting. SpliceAI predicts no splicing impact (max delta = 0.00), supporting that this variant does not alter splicing. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu1201=)
  • no amino acid change
  • SpliceAI max delta = 0.00
  • no predicted splice impact
Sources
spliceai ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

PP3 PP3 is not met for this synonymous variant. The InSiGHT MSH6 VCEP PP3 rules require a missense variant with HCI prior >0.68 or a predicted splice defect with SpliceAI delta ≥0.2 for non-canonical splice sites. This variant is synonymous, has no HCI prior score (not in the MSH6 HCI-PRIORS table), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no predicted splice defect)
  • HCI prior not found for this synonymous variant
Sources
spliceai ↗vcep_hci_priors_msh6cspec ↗
BA1 The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is well below the InSiGHT MSH6 VCEP BA1 Stand Alone threshold of ≥0.0022 (0.22%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.2 × 10⁻⁷
  • threshold for BA1 is ≥0.0022
Sources
gnomad_v4 ↗cspec ↗
BS1 The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is below the InSiGHT MSH6 VCEP BS1 Strong threshold of ≥0.00022 (0.022%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.2 × 10⁻⁷
  • threshold for BS1 is ≥0.00022
Sources
gnomad_v4 ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo observations have been reported for NM_000179.3:c.3603C>A. The variant is absent from ClinVar and no publications describe de novo occurrence. Details ▾Hide ▴
Still missing
  • No de novo data available in ClinVar or literature.
PS3 No calibrated functional assay data are available for NM_000179.3:c.3603C>A. The variant was not found in the MMR functional assay SVI documentation spreadsheet (Functional-assay-SVI-documentation-MMR.xlsx). Details ▾Hide ▴
Still missing
  • No functional assay data for this specific variant.
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for NM_000179.3:c.3603C>A. No pedigrees or Bayes likelihood ratios have been reported. Details ▾Hide ▴
Still missing
  • No co-segregation data available.
PP4 No tumor phenotype data (MSI-H status, MMR IHC) are available for NM_000179.3:c.3603C>A. PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Still missing
  • No tumor MSI/IHC phenotype data available.
BS2 No data are available regarding co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. Details ▾Hide ▴
Still missing
  • No co-occurrence in trans data available.
BS3 No calibrated functional assay data are available for NM_000179.3:c.3603C>A to assess normal protein function. The variant was not found in the MMR functional assay SVI documentation. Details ▾Hide ▴
Still missing
  • No functional assay data for this specific variant.
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No co-segregation or lack-of-segregation data available.
BP5 No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, MLH1 methylation) are available for NM_000179.3:c.3603C>A. Details ▾Hide ▴
Still missing
  • No tumor phenotype data available.
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000179.3:c.3603C>A is a synonymous variant (p.Leu1201=) and does not introduce a premature termination codon, alter a canonical splice site, or produce a null allele. PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2) under the InSiGHT MSH6 VCEP v2.0.0. Details ▾Hide ▴
Evidence considered
  • Synonymous substitution
  • no null variant mechanism.
Sources
cspec ↗pvs1_variant_assessment
PS1 N/AThis is a synonymous variant, not a missense substitution. PS1 requires a nucleotide change that encodes the same amino acid as a previously established Pathogenic or Likely Pathogenic missense variant. Synonymous changes are not eligible. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PS1 requires missense change at protein level.
Sources
cspec ↗
PS4 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates PS4 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates PM1 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been classified as Pathogenic. This is a synonymous variant and PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PM5 requires missense change.
Sources
cspec ↗pm5_candidates
PM6 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates PM6 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates PP2 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates PP5 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates BP1 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP2 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates BP2 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPSkipped — trivially not applicable per instructions. The InSiGHT MSH6 VCEP designates BP3 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPThe InSiGHT MSH6 VCEP v2.0.0 designates BP6 as Not Applicable for this VCEP. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/APS5 is not defined in the InSiGHT MSH6 VCEP v2.0.0 criteria set, and this variant is absent from ClinVar with no reputable source asserting a pathogenic classification. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source classifies as pathogenic.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
MSH6
Transcript
NM_000179.3
Coding (HGVS c.)
NM_000179.3:c.3603C>A
Protein (HGVS p.)
NP_000170.1:p.(Leu1201=)
GRCh38
chr2:47805664 C>A
GRCh37
chr2:48032803 C>A

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 1 / 1,613,414 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 / 1,613,414 alleles · 0 hom
European (non-Finnish)1 / 1,179,594 8.5e-07
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.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47749e-07; MAF= 0.00008%, 1/1179594 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Under the InSiGHT MSH6 VCEP v2.0.0 BP4 rule, synonymous variants with SpliceAI delta ≤0.1 meet BP4_Supporting. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu1201=)
  • SpliceAI max delta = 0.00 (≤0.1 threshold for BP4_Supporting)
Sources
spliceai ↗cspec ↗
BP7 SupportingNM_000179.3:c.3603C>A is a synonymous (silent) variant (p.Leu1201=). Under the InSiGHT MSH6 VCEP v2.0.0, synonymous variants meet BP7_Supporting. SpliceAI predicts no splicing impact (max delta = 0.00), supporting that this variant does not alter splicing. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu1201=)
  • no amino acid change
  • SpliceAI max delta = 0.00
  • no predicted splice impact
Sources
spliceai ↗cspec ↗
PP3 PP3 is not met for this synonymous variant. The InSiGHT MSH6 VCEP PP3 rules require a missense variant with HCI prior >0.68 or a predicted splice defect with SpliceAI delta ≥0.2 for non-canonical splice sites. This variant is synonymous, has no HCI prior score (not in the MSH6 HCI-PRIORS table), and SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no predicted splice defect)
  • HCI prior not found for this synonymous variant
Sources
spliceai ↗vcep_hci_priors_msh6cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 1 / 1,613,414 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 Captured ClinVar source record 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= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47749e-07; MAF= 0.00008%, 1/1179594 alleles, homozygotes = 0).

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 = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.