Variant classification summary

NM_000179.3:c.3603C>A

MSH6 · NP_000170.1:p.(Leu1201=) · NM_000179.3

GRCh37: chr2:48032803 C>A · GRCh38: chr2:47805664 C>A

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Leu1201=)

gnomAD AF

6.198037205577738e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.3:c.3603C>A (p.Leu1201=) is a synonymous variant in MSH6 exon 7. SpliceAI predicts no splicing impact (delta = 0.00). The variant is extremely rare in gnomAD v4.1 (1/1,613,414 alleles; AF = 6.2 × 10⁻⁷) and absent from gnomAD v2.1, gnomAD-Canada, ClinVar, and COSMIC.

2

Under the InSiGHT MSH6 VCEP v2.0.0: BP7_Supporting is met because this is a synonymous variant. BP4_Supporting is met because SpliceAI delta (0.00) ≤ 0.1. PM2_Supporting is met because the variant allele frequency (6.2 × 10⁻⁷) is below the VCEP threshold of <0.00002.

3

Per the InSiGHT VCEP combining rules, two Benign Supporting criteria (BP4_Supporting + BP7_Supporting) with one Pathogenic Supporting criterion (PM2_Supporting) results in Uncertain Significance (VUS) — Rule31 (≥1 Benign.Supporting + ≥1 Pathogenic.Supporting → VUS Conflicting) takes precedence over Rule19 (≥2 Benign.Supporting → Likely Benign).

4

PVS1, PS1, PM5, PS4, PP2, PP5, PM1, PM6, BP1, BP2, BP3, BP6 are not applicable. PS2, PS3, PP1, PP4, BS2, BS3, BS4, BP5 are not assessed due to absence of de novo, functional, tumor phenotype, co-segregation, or co-occurrence data.

Final determination: Rule19 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 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	NM_000179.3:c.3603C>A is a synonymous variant (p.Leu1201=) and does not introduce a premature termination codon, alter a canonical splice site, or produce a null allele. PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2) under the InSiGHT MSH6 VCEP v2.0.0.	cspec pvs1_variant_assessment
PS1	N/A	This is a synonymous variant, not a missense substitution. PS1 requires a nucleotide change that encodes the same amino acid as a previously established Pathogenic or Likely Pathogenic missense variant. Synonymous changes are not eligible.	cspec
PS2	Not assessed	No de novo observations have been reported for NM_000179.3:c.3603C>A. The variant is absent from ClinVar and no publications describe de novo occurrence.
PS3	Not assessed	No calibrated functional assay data are available for NM_000179.3:c.3603C>A. The variant was not found in the MMR functional assay SVI documentation spreadsheet (Functional-assay-SVI-documentation-MMR.xlsx).	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates PS4 as Not Applicable.	cspec
PS5	N/A	PS5 is not defined in the InSiGHT MSH6 VCEP v2.0.0 criteria set, and this variant is absent from ClinVar with no reputable source asserting a pathogenic classification.	cspec clinvar
PM1	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates PM1 as Not Applicable.	cspec
PM2	Met	NM_000179.3:c.3603C>A is extremely rare in population databases. In gnomAD v4.1 it is observed in 1 of 1,613,414 alleles (AF = 6.2 × 10⁻⁷), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change has been classified as Pathogenic. This is a synonymous variant and PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates PM6 as Not Applicable.	cspec
PP1	Not assessed	No co-segregation data are available for NM_000179.3:c.3603C>A. No pedigrees or Bayes likelihood ratios have been reported.
PP2	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates PP2 as Not Applicable.	cspec
PP3	Not met	PP3 is not met for this synonymous variant. The InSiGHT MSH6 VCEP PP3 rules require a missense variant with HCI prior >0.68 or a predicted splice defect with SpliceAI delta ≥0.2 for non-canonical splice sites. This variant is synonymous, has no HCI prior score (not in the MSH6 HCI-PRIORS table), and SpliceAI predicts no splicing impact (max delta = 0.00).	spliceai vcep_hci_priors_msh6 cspec
PP4	Not assessed	No tumor phenotype data (MSI-H status, MMR IHC) are available for NM_000179.3:c.3603C>A. PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location.
PP5	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates PP5 as Not Applicable.	cspec
BA1	Not met	The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is well below the InSiGHT MSH6 VCEP BA1 Stand Alone threshold of ≥0.0022 (0.22%).	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is below the InSiGHT MSH6 VCEP BS1 Strong threshold of ≥0.00022 (0.022%).	gnomad_v4 cspec
BS2	Not assessed	No data are available regarding co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3	Not assessed	No calibrated functional assay data are available for NM_000179.3:c.3603C>A to assess normal protein function. The variant was not found in the MMR functional assay SVI documentation.	vcep_functional_assay_svi_documentation_mmr
BS4	Not assessed	No co-segregation data are available to assess lack of segregation with disease.
BP1	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates BP1 as Not Applicable.	cspec
BP2	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates BP2 as Not Applicable.	cspec
BP3	N/A	Skipped — trivially not applicable per instructions. The InSiGHT MSH6 VCEP designates BP3 as Not Applicable.	cspec
BP4	Met	SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Under the InSiGHT MSH6 VCEP v2.0.0 BP4 rule, synonymous variants with SpliceAI delta ≤0.1 meet BP4_Supporting.	spliceai cspec
BP5	Not assessed	No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, MLH1 methylation) are available for NM_000179.3:c.3603C>A.
BP6	N/A	The InSiGHT MSH6 VCEP v2.0.0 designates BP6 as Not Applicable for this VCEP.	cspec
BP7	Met	NM_000179.3:c.3603C>A is a synonymous (silent) variant (p.Leu1201=). Under the InSiGHT MSH6 VCEP v2.0.0, synonymous variants meet BP7_Supporting. SpliceAI predicts no splicing impact (max delta = 0.00), supporting that this variant does not alter splicing.	spliceai cspec

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