Variant classification summary

NM_000179.3:c.1054G>A

MSH6 · NP_000170.1:p.(Val352Ile) · NM_000179.3

GRCh37: chr2:48026176 G>A · GRCh38: chr2:47799037 G>A

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BP4 supporting benign

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Val352Ile)

gnomAD AF

9.293426944990347e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.3(MSH6):c.1054G>A (p.Val352Ile) is a missense substitution in exon 4 of MSH6.

2

This variant has been observed in gnomAD v4.1 at an overall allele frequency of 0.000093 (150/1,614,044 alleles, 1 homozygote), with a grpmax filtering allele frequency of 0.000199 (0.0199%). In gnomAD v2.1 the variant is present at an allele frequency of 0.000074 (21/282,596 alleles, 1 homozygote). It is absent from gnomAD-Canada v1.0.

3

The gnomAD v4.1 grpmax FAF (0.000199) is below the InSiGHT MSH6 VCEP BS1 threshold of ≥0.00022 and far below the BA1 threshold of ≥0.0022, so neither allele-frequency-based benign criterion is met. The overall allele frequency also exceeds the PM2 supporting threshold of <0.00002, so PM2 is not met.

4

Computational predictors strongly favor a benign effect: the HCI prior probability for pathogenicity is 0.0007 (far below the BP4_Supporting threshold of <0.11), SpliceAI predicts no splicing impact (max delta 0.00), REVEL score is 0.216, and BayesDel score is -0.443.

5

The variant was detected as a somatic finding in a tumor from a suspected Lynch syndrome patient (PMID:25111426), where it was classified as class 2 (likely not pathogenic) with 34% variant allele frequency, retention of heterozygosity, and normal MMR protein expression by IHC. This somatic observation is consistent with a benign or low-impact variant but does not independently meet any VCEP criterion in a germline context.

6

In ClinVar, this variant is reported as Likely benign by 9 clinical laboratories, Uncertain significance by 4, and Benign by 1 (ClinVar Variation ID: 182617). The InSiGHT expert panel has not issued a classification for this variant.

7

No pathogenic or likely pathogenic missense variants at the same amino acid residue (Val352) were identified in InSiGHT VCEP records, so PM5 cannot be assessed.

8

Applying the InSiGHT MSH6 VCEP version 2.0.0 combining rules: BP4_Supporting is the only criterion met. With a single benign supporting criterion, neither the Likely Benign threshold (≥2 benign supporting per Rule 19, or 1 benign strong + 1 benign supporting per Rule 18) nor any pathogenic threshold is reached. The variant is classified as Uncertain Significance.

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	Missense substitution (p.Val352Ile); does not meet InSiGHT MSH6 VCEP PVS1 criteria, which require nonsense/frameshift PTC ≤ codon 1341, canonical splice site alteration, large genomic alteration, or confirmed splicing aberration.	pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic variant encoding the same amino acid change (Val352Ile) via a different nucleotide change was identified in InSiGHT MSH6 VCEP records.
PS2	Not assessed	No de novo observation data available for this variant.
PS3	Not met	No calibrated functional assay data available in the VCEP MMR functional assay documentation. In silico scores (REVEL 0.216, BayesDel -0.443, HCI prior 0.0007) do not support a pathogenic functional effect.	revel bayesdel hci_prior
PS4	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
PS5	N/A	Criterion not defined in the InSiGHT MSH6 VCEP framework.
PM1	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
PM2	Not met	gnomAD v4.1 allele frequency 0.000093 (150/1,614,044 alleles) exceeds the InSiGHT MSH6 VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles). The variant also has one homozygote in gnomAD v4.1 and one homozygote in gnomAD v2.1.	gnomad_v4
PM5	Not assessed	No pathogenic or likely pathogenic missense variant at the same amino acid residue (Val352) identified in InSiGHT MSH6 VCEP records. PM5 candidate search returned zero same-residue comparator variants.	pm5_candidates
PM6	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
PP1	Not assessed	No co-segregation data available for this variant.
PP2	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
PP3	Not met	HCI prior probability for pathogenicity 0.0007 is far below the InSiGHT MSH6 VCEP PP3_Moderate threshold (>0.81) and PP3_Supporting threshold (>0.68). SpliceAI max delta score 0.00 is below the PP3_Supporting threshold for non-canonical splice variants (≥0.2). REVEL score 0.216 and BayesDel score -0.443 do not support a pathogenic prediction.	hci_prior spliceai revel bayesdel
PP4	Not assessed	No tumor phenotype data (MSI status, MMR IHC) specific to this germline variant available in evidence sources.
PP5	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications. InSiGHT expert panel has not classified this variant.
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency 0.000199 (0.0199%) is below the InSiGHT MSH6 VCEP BA1 threshold of ≥0.0022 (0.22%).	gnomad_v4
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency 0.000199 (0.0199%) is slightly below the InSiGHT MSH6 VCEP BS1 threshold of ≥0.00022 (0.022%).	gnomad_v4
BS2	Not assessed	No trans co-occurrence data with a known pathogenic MSH6 variant available.
BS3	Not assessed	No calibrated functional assay data available for this variant in the VCEP MMR functional assay documentation. No variant-specific functional studies identified in the literature.
BS4	Not assessed	No co-segregation data available for this variant.
BP1	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
BP2	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
BP3	N/A	Substitution variant; BP3 applies to in-frame deletions/insertions.
BP4	Met	HCI prior probability for pathogenicity 0.0007 falls below the InSiGHT MSH6 VCEP BP4_Supporting threshold of <0.11. SpliceAI max delta score 0.00 confirms no predicted splicing impact. REVEL score 0.216 and BayesDel score -0.443 are also consistent with a benign computational profile.	hci_prior spliceai revel bayesdel
BP5	Not assessed	No tumor phenotype data (MSS/MSI status, MMR IHC) from germline carriers of this variant available. A somatic observation in a tumor with normal MMR protein expression was reported (PMID:25111426) but does not independently meet BP5 criteria in a germline context.
BP6	N/A	Criterion not for use per InSiGHT MSH6 VCEP specifications.
BP7	N/A	Missense substitution (p.Val352Ile); BP7 requires a synonymous (silent) or intronic variant at or beyond -21/+7.
PM3	N/A	Substitution variant; PM3 assessment requires specific trans configuration data relevant to recessive conditions.
PM4	N/A	Substitution variant; PM4 applies to non-in-frame deletions/insertions causing protein length change.

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