Variant classification summary

NM_000179.3:c.1822A>G

MSH6 · NP_000170.1:p.(Ile608Val) · NM_000179.3

GRCh37: chr2:48026944 A>G · GRCh38: chr2:47799805 A>G

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ile608Val)

gnomAD AF

6.195303216725337e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.3:c.1822A>G (p.Ile608Val) is a missense variant in exon 4 of MSH6. Only one criterion is met: BP4_supporting based on an HCI prior probability of 0.0038 (<0.11), with concordant in silico predictions (REVEL 0.185, BayesDel -0.360, SpliceAI Δ=0.01). All other applicable criteria are not met, and no pathogenic criteria are met.

2

This variant has been observed in gnomAD v4.1 at a grpmax FAF of 6.393e-05 (100/1,614,126 alleles, 0 homozygotes), which is above the VCEP PM2_supporting threshold of 0.00002 but below the benign BA1 (0.0022) and BS1 (0.00022) thresholds. The variant is present at low frequency in population databases, consistent with a rare variant of uncertain significance.

3

This variant has been reported in ClinVar as Uncertain significance by 10 of 11 clinical submitters and as Likely benign by 1 submitter (ClinVar Variation ID: 182626). No expert panel classification exists, and the review status is 'criteria provided, single submitter.' The variant has not been reported in COSMIC.

4

No functional assay data are available for this variant in the InSiGHT MMR calibrated functional assay documentation. The variant was predicted to have 'no impact on MSH6' by the CoDP in silico tool (score 0.033; PMID:23621914), but this is computational prediction, not experimental functional evidence.

5

Overall, NM_000179.3:c.1822A>G (p.Ile608Val) is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MSH6 VCEP v2.0 framework. Only BP4_supporting is met; all other applicable criteria are not met. No pathogenic criteria are met, and no benign criteria beyond BP4_supporting apply.

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 v2.0 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 to missense variants. NM_000179.3:c.1822A>G is a missense substitution (p.Ile608Val) and does not fall into any PVS1 null-variant bucket per the InSiGHT MSH6 VCEP v2.0 framework (nonsense, frameshift, canonical splice, initiation codon, or exon-level deletion).	pvs1_variant_assessment cspec
PS1	Not met	No different underlying nucleotide change encoding the same amino acid substitution (p.Ile608Val) has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MSH6 VCEP. The variant is absent from the VCEP pilot variants spreadsheet and no such comparator was identified in ClinVar or the literature.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not met	No de novo observations were identified for NM_000179.3:c.1822A>G in the available evidence. The InSiGHT MSH6 VCEP requires de novo points derived from confirmed parentage in MMR-deficient tumors; zero de novo events are documented.	cspec
PS3	Not met	No calibrated functional assay data exist for NM_000179.3:c.1822A>G (p.Ile608Val). The InSiGHT MMR functional assay SVI documentation does not include this variant. One publication (PMID:23621914) provided an in silico CoDP prediction score of 0.033, classifying it as having 'no impact on MSH6,' but in silico prediction does not constitute experimental functional evidence for PS3 under the VCEP framework.	vcep_functional_assay_svi_documentation_mmr cspec
PS4	N/A	PS4 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework.	cspec
PS5	N/A	PS5 is not included in the InSiGHT MSH6 VCEP v2.0 criteria set and is not applicable in this framework.	cspec
PM1	N/A	PM1 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework.	cspec
PM2	Not met	PM2_supporting requires gnomAD v4 grpmax filtering allele frequency < 0.00002 (<1 in 50,000 alleles) per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which exceeds the threshold. The variant is present in 100/1,614,126 alleles in gnomAD v4.1 and 8/281,964 alleles in gnomAD v2.1, indicating it is not absent or extremely rare.	gnomad_v4 cspec
PM5	Not met	PM5 requires a different missense change at the same amino acid residue (Ile608) classified as Pathogenic or Likely Pathogenic by the VCEP, AND PP3 must be supporting. PP3 is not met (HCI prior = 0.0038, well below the 0.68 threshold). Additionally, no Pathogenic/Likely Pathogenic same-residue comparator was identified in the VCEP pilot variants or ClinVar at Ile608.	pm5_candidates cspec hci_prior
PM6	N/A	PM6 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework.	cspec
PP1	Not met	No co-segregation data are available for NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires a combined Bayes Likelihood Ratio from segregation analysis in pedigrees; no such data exist in the evidence.	cspec
PP2	N/A	PP2 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP notes that 'missense variant in a gene with low rate of benign missense changes does not apply' for MSH6.	cspec
PP3	Not met	PP3 requires HCI prior probability > 0.68 for supporting or > 0.81 for moderate per InSiGHT MSH6 VCEP. The HCI prior probability for p.Ile608Val is 0.0038, which is well below both thresholds. Additional in silico evidence confirms a benign profile: REVEL score 0.185, BayesDel score -0.360, SpliceAI max delta 0.01.	hci_prior revel bayesdel spliceai cspec
PP4	Not met	No tumor data (MSI status or MMR IHC) are available for patients carrying NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires CRC/endometrial tumors with MSI-H and/or loss of MMR protein expression consistent with the variant location.	cspec
PP5	N/A	PP5 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP explicitly marks this criterion as 'Not Applicable for this VCEP' per ClinGen SVI VCEP Review Committee recommendation.	cspec
BA1	Not met	BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%) per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which is far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022 per InSiGHT MSH6 VCEP. The observed grpmax FAF is 6.393e-05 (0.0064%), which is below the BS1 lower 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 without CMMRD features. The InSiGHT MSH6 VCEP requires confirmed phase through parental testing.	cspec
BS3	Not met	No calibrated functional assay data demonstrate proficient MMR function (functional odds ≤ 0.05 for BS3_strong or ≤ 0.48 for BS3_supporting) for NM_000179.3:c.1822A>G. The InSiGHT MMR functional assay SVI documentation does not include this variant. The in silico CoDP score of 0.033 from PMID:23621914 predicts no impact but does not constitute a validated functional assay.	vcep_functional_assay_svi_documentation_mmr cspec
BS4	Not met	No lack-of-segregation data are available. The InSiGHT MSH6 VCEP requires combined Bayes Likelihood Ratio from pedigrees demonstrating absence of co-segregation.	cspec
BP1	N/A	BP1 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP notes 'missense variant in a gene where only loss of function causes disease is not applicable' for MSH6.	cspec
BP2	N/A	BP2 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework.	cspec
BP4	Met	BP4_supporting is met under the InSiGHT MSH6 VCEP v2.0: the HCI prior probability for pathogenicity is 0.0038, which is below the <0.11 threshold. Multiple independent in silico predictors support a benign interpretation: REVEL score 0.185 (low pathogenicity), BayesDel score -0.360 (benign), and SpliceAI max delta 0.01 (no predicted splicing impact).	hci_prior revel bayesdel spliceai cspec
BP5	Not met	No tumor data (MSS status or MMR IHC) are available for patients carrying NM_000179.3:c.1822A>G. The InSiGHT MSH6 VCEP requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in MSI-H tumors, to apply BP5.	cspec
BP6	N/A	BP6 is not applicable under the InSiGHT MSH6 VCEP v2.0 framework. The VCEP explicitly marks this criterion as 'Not Applicable for this VCEP' per ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	Not met	BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000179.3:c.1822A>G is a missense variant (p.Ile608Val) and does not meet the BP7 criteria.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a missense substitution.	cspec
PM3	N/A	Skipped per adjudication instructions — trivially not applicable.
PM4	N/A	Skipped per adjudication instructions — trivially not applicable.

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