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MSH6
Final classification
VUS
MSH6 c.3602_3606delinsAA · p.Leu1201_Met1202delinsGln
MSH6

NM_000179.3:c.3602_3606delinsAA is an in-frame deletion-insertion in MSH6 exon 7, resulting in the substitution of leucine 1201 and methionine 1202 with a single glutamine residue (p.Leu1201_Met1202delinsGln).

Gene
MSH6
Transcript
NM_000179.3
HGVS · transcript:coding
NM_000179.3:c.3602_3606delinsAA
Consequence
N/A
GRCh38
chr2:47805663 TCATG>AA
GRCh37
chr2:48032802 TCATG>AA
Basis 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.
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.
Classification rationale
PM2 VUS
MSH6 c.3602_3606delinsAA

NM_000179.3:c.3602_3606delinsAA is an in-frame deletion-insertion in MSH6 exon 7, resulting in the substitution of leucine 1201 and methionine 1202 with a single glutamine residue (p.Leu1201_Met1202delinsGln).1 This variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency <0.00002 (1 in 50,000 alleles).2 The variant is absent from ClinVar with no submissions from any laboratory.3 No functional data, segregation data, tumor phenotype data, or literature reports are available for this variant. The variant has not been tested in any MSH6 VCEP-calibrated functional assay.4 PVS1 is not met because this in-frame delins does not introduce a premature termination codon and does not meet any PVS1 rule under the MSH6 VCEP specification (v2.0.0), which requires a nonsense, frameshift, or canonical splice variant.5 With only PM2_Supporting met and no other criteria applicable, the variant is classified as a Variant of Uncertain Significance under the ClinGen InSiGHT MSH6 VCEP combination rules (v2.0.0).6

PM2 VUS
4 clinvar ↗vcep_functional_assay_svi_documentation_mmroncokb ↗
5 cspec ↗pvs1_variant_assessment
6 cspec ↗final_classification_framework
Gene diagram · NM_000179.3 · variants mapped to exon structure
MSH6 NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
NM_000179.3:c.3602_3606delinsAA is absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). The variant is also absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Absent from gnomAD v4.1 (0/0 allelesAF <0.00002)also absent from v2.1 and gnomAD-Canada
Assessed · not applied
Pathogenic
PVS1 NM_000179.3:c.3602_3606delinsAA is an in-frame deletion-insertion (5 bp deleted, 2 bp inserted; net -3 bp) resulting in p.(Leu1201_Met1202delinsGln).
PS1 PS1 applies to missense substitutions encoding the same amino acid change as an established pathogenic variant, or to variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant.
PS2 No de novo observations have been reported for this variant.
PS3 No functional data exists for NM_000179.3:c.3602_3606delinsAA.
PP1 No co-segregation data is available for this variant.
PP3 Under the MSH6 VCEP, PP3 is applicable only to missense variants with HCI prior probability >0.68 or to non-canonical splice variants with SpliceAI delta ≥0.2.
PP4 No tumor phenotype data is available for this variant.
Benign
BA1 The variant is absent from gnomAD v4.1 with a grpmax filtering allele frequency of 0%, well below the MSH6 VCEP BA1 threshold of ≥0.0022 (0.22%).
BS1 The variant is absent from gnomAD v4.1.
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 and without CMMRD features.
BS3 No functional data demonstrating proficient MMR function for this variant.
BS4 No segregation or lack-of-segregation data is available for this variant.
BP4 Under the MSH6 VCEP, BP4 applies only to missense variants with HCI prior probability <0.11 or to intronic/synonymous variants with SpliceAI delta ≤0.1.
BP5 No tumor data demonstrating MSS status or retained MMR protein expression inconsistent with the variant gene is available.
N/A · 13 PS4 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico No data
No in-silico prediction was recorded for this variant.
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots