Variant classification summary

NM_000179.3:c.3602_3606delinsAA

MSH6 · NP_000170.1:p.(Leu1201_Met1202delinsGln) · NM_000179.3

GRCh37: chr2:48032802 TCATG>AA · GRCh38: chr2:47805663 TCATG>AA

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Leu1201_Met1202delinsGln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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).

3

The variant is absent from ClinVar with no submissions from any laboratory.

4

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.

5

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.

6

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).

Final determination: No criteria-combination rule matched the adjudicated criteria in the 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 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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). It does not introduce a premature termination codon, is not a frameshift or nonsense variant, and does not disrupt a canonical splice site. Under the ClinGen InSiGHT MSH6 VCEP specification (v2.0.0), PVS1 at any strength requires a nonsense/frameshift PTC ≤ codon 1341 (Very Strong) or between codons 1342-1360 (Moderate), a canonical ±1,2 splice variant, or an initiation codon variant. This in-frame delins does not meet any PVS1 rule.	cspec pvs1_variant_assessment
PS1	Not met	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. This variant is an in-frame delins, not a missense substitution, and does not involve a splice site. No applicable PS1 comparator exists.	cspec
PS2	Not met	No de novo observations have been reported for this variant. The literature screen identified zero publications, and ClinVar contains no submissions for this variant.	clinvar
PS3	Not met	No functional data exists for NM_000179.3:c.3602_3606delinsAA. The variant is absent from the MSH6 VCEP-calibrated functional assays (Drost 2018/2020 CIMRA, Jia 2021/Scott 2022 saturation mutagenesis, Rath 2022, Thompson 2013, Morak 2019, Bouvet 2019). OncoKB reports unknown oncogenic effect with no variant-specific curated functional evidence. No published experimental characterization of this exact variant or a systematically characterized range that includes it was identified.	oncokb vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
PS5	Not met	No publications or ClinVar submissions associate NM_000179.3:c.3602_3606delinsAA with disease. The variant is absent from ClinVar and no literature reports were identified in the literature triage pass.	clinvar
PM1	N/A	PM1 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
PM2	Met	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.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
PM5	N/A	PM5 under the MSH6 VCEP applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic or Likely Pathogenic. This variant is an in-frame delins, not a missense substitution, and is not eligible for classic same-residue PM5 assessment.	cspec pm5_candidates
PM6	N/A	PM6 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
PP1	Not met	No co-segregation data is available for this variant. No family studies or pedigrees have been reported in ClinVar or the literature.	clinvar
PP2	N/A	PP2 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
PP3	Not met	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. This variant is an in-frame delins and does not fall into either category. No REVEL, BayesDel, HCI prior, or SpliceAI scores are available for this variant type.	cspec spliceai vcep_hci_priors_msh6
PP4	Not met	No tumor phenotype data is available for this variant. No MSI-H tumors with loss of MMR protein expression consistent with MSH6 have been reported in association with this variant in ClinVar or the literature.	clinvar
PP5	N/A	PP5 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
BA1	Not met	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%). An allele frequency this low does not support a stand-alone benign classification.	gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4.1. The MSH6 VCEP BS1 threshold is a grpmax filtering allele frequency of ≥0.00022 (0.022%) and <0.0022 (0.22%). The observed AF of 0% does not meet this threshold.	gnomad_v4 cspec
BS2	Not met	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. No such cases have been reported in ClinVar or the literature.	clinvar
BS3	Not met	No functional data demonstrating proficient MMR function for this variant. The variant has not been tested in any of the MSH6 VCEP-calibrated functional assays (CIMRA, saturation mutagenesis, cell survival, or splicing assays).	vcep_functional_assay_svi_documentation_mmr oncokb
BS4	Not met	No segregation or lack-of-segregation data is available for this variant. No family pedigrees have been reported.	clinvar
BP1	N/A	BP1 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
BP2	N/A	BP2 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
BP3	N/A	BP3 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
BP4	Not met	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. This variant is an in-frame delins and does not fall into either category. No computational evidence supports a benign interpretation.	cspec vcep_hci_priors_msh6 spliceai
BP5	Not met	No tumor data demonstrating MSS status or retained MMR protein expression inconsistent with the variant gene is available. No CRC or endometrial tumors have been reported in association with this variant.	clinvar
BP6	N/A	BP6 is designated Not Applicable by the ClinGen InSiGHT MSH6 VCEP specification v2.0.0.	cspec
BP7	N/A	BP7 under the MSH6 VCEP applies only to synonymous (silent) or intronic variants at or beyond -21/+7. This variant is an in-frame deletion-insertion in exon 7 and does not meet the BP7 criteria.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.