Variant classification summary

NM_000179.2:c.440T>G

MSH6 · NP_000170.1:p.(Leu147Arg) · NM_000179.2

GRCh37: chr2:48018245 T>G · GRCh38: chr2:47791106 T>G

Gene: MSH6 Transcript: NM_000179.2

Final call

VUS

PM2 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.2

Protein

NP_000170.1:p.(Leu147Arg)

gnomAD AF

6.195594932003346e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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.

3

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

4

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.

5

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.

6

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

7

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.

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	N/A	PVS1 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).	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	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.	vcep_vcep_pilot_variants_mmr
PS2	Not met	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.
PS3	Not met	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.	oncokb vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
PS5	N/A	PS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the InSiGHT MSH6 VCEP specifications.
PM1	N/A	PM1 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
PM2	Met	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).	gnomad_v4
PM5	Not met	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.	pm5_candidates vcep_vcep_pilot_variants_mmr
PM6	N/A	PM6 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
PP1	Not met	No cosegregation data are available for this variant. The InSiGHT MSH6 VCEP requires Bayes likelihood ratio calculations from pedigrees, and none have been reported.
PP2	N/A	PP2 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
PP3	Not met	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.	hci_prior revel bayesdel spliceai
PP4	Not met	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.
PP5	N/A	PP5 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
BA1	Not met	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.	gnomad_v4
BS1	Not met	The gnomAD v4.1 allele frequency (6.20e-07) is below the InSiGHT MSH6 VCEP BS1_Strong lower bound of ≥0.00022 (0.022%).	gnomad_v4
BS2	Not met	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.
BS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr oncokb
BS4	Not met	No lack-of-cosegregation data are available. The InSiGHT MSH6 VCEP requires Bayes likelihood ratio calculations demonstrating absence of cosegregation with disease.
BP1	N/A	BP1 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
BP2	N/A	BP2 is designated Not Applicable by the InSiGHT MSH6 VCEP (v2.0.0).	cspec
BP3	N/A	BP3 is a trivially skipped criterion (in-frame indels in repetitive regions); not applicable to a missense substitution.
BP4	Not met	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.	hci_prior revel bayesdel spliceai
BP5	Not met	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.
BP6	N/A	BP6 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.	cspec
BP7	N/A	BP7 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.

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.