LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-04
Case ID: NM_000179.3_c.3556_1G_C_20260504_145056
Framework: ACMG/AMP 2015
Variant classification summary

NM_000179.3:c.3556+1G>C

MSH6  · NP_000170.1:p.?  · NM_000179.3
GRCh37: chr2:48032167 G>C  ·  GRCh38: chr2:47805028 G>C
Gene: MSH6 Transcript: NM_000179.3
Final call
VUS
PM2 supporting PVS1 very strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH6
Transcript
NM_000179.3
Protein
NP_000170.1:p.?
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The MSH6 NM_000179.3:c.3556+1G>C (NP_000170.1:p.?) variant has been reported in ClinVar as Pathogenic by a single clinical laboratory.
2
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002.
3
This canonical +1 splice-donor variant is predicted to disrupt splicing, with SpliceAI showing a maximum delta score of 1.00, and the MSH6 VCEP PVS1 framework supports very strong pathogenic evidence for canonical splice variants expected to cause a frameshifting transcript subject to nonsense-mediated decay.
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
BA1 Not met The gnomAD v4.1 total allele frequency is 1.24445e-06 (0.00012%), which is below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%), so this frequency does not support a benign stand-alone classification.
gnomad_v4 cspec
BS2 Not assessed No evidence was identified showing this variant in trans with a known pathogenic MSH6 variant in an individual meeting the VCEP BS2 conditions and lacking evidence of CMMRD.
cspec vcep_table_for_cmmrd_diagnosis
BP6 N/A BP6 is not used in the MSH6 VCEP framework.
cspec
PP4 Not assessed No microsatellite instability or mismatch repair immunohistochemistry data were identified for this variant, so the tumor phenotype-specific PP4 rule cannot be applied.
cspec
PP1 Not assessed No segregation data were identified, so there is no Bayes likelihood ratio available to support PP1.
cspec
BS1 Not met The highest observed gnomAD v4.1 population allele frequency is 1.60653e-05 (0.00161%) in Remaining individuals, which is below the BS1 range of 0.00022 to <0.0022, so the population data do not support BS1.
gnomad_v4 cspec
BP7 Not met This intronic variant is at the +1 canonical splice donor position, not at or beyond the BP7 boundary of +7, so it does not meet the MSH6 VCEP BP7 rule.
cspec
PP2 N/A PP2 is not used in the MSH6 VCEP framework.
cspec
BP3 N/A BP3 is not used in the MSH6 VCEP framework.
cspec
BP1 N/A BP1 is not used in the MSH6 VCEP framework.
cspec
BS3 Not assessed No RNA or functional assay evidence was identified showing normal splicing or preserved MSH6 function for this variant, so BS3 cannot be applied.
cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PM2 Met This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a total allele frequency of 1.24445e-06 (2/1,607,140 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength.
gnomad_v2 gnomad_v4 cspec
BP4 Not met SpliceAI predicts a strong splice effect with a max delta score of 1.00, which is above the MSH6 VCEP BP4 no-impact threshold of 0.1 for intronic variants. A BayesDel score of 0.325996 is available, but it does not overcome the splice prediction evidence and does not satisfy the VCEP BP4 rule.
spliceai bayesdel cspec
PS1 N/A This variant is a canonical splice-donor change and no applicable same-amino-acid or same non-canonical splice-nucleotide comparator rule is available for PS1 in the MSH6 VCEP framework.
cspec
PS2 Not assessed No de novo data were identified for this variant, so PS2 cannot be applied.
cspec
BP5 Not assessed No tumor findings inconsistent with MSH6-related disease were identified, so BP5 was not applied.
cspec
PVS1 Met This variant affects the canonical +1 splice donor position of MSH6. The MSH6 VCEP PVS1 rule allows very strong evidence for IVS±1/2 variants when the predicted splice outcome disrupts the reading frame and is expected to undergo nonsense-mediated decay, and the affected donor corresponds to exon 6, whose skipping would be out of frame. SpliceAI also predicts a strong splice effect with a max delta score of 1.00, supporting disruption of normal splicing.
cspec pvs1_gene_context pvs1_variant_assessment spliceai
PP5 N/A PP5 is not used in the MSH6 VCEP framework.
cspec
BP2 N/A BP2 is not used in the MSH6 VCEP framework.
cspec
PS4 N/A PS4 is not used in the MSH6 VCEP framework.
cspec
PM4 N/A PM4 is not used in the MSH6 VCEP framework.
cspec
PS3 Not assessed No validated RNA study or calibrated functional assay was identified for this exact variant showing an abnormal MSH6 effect, so PS3 cannot be applied at this time.
cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PP3 N/A SpliceAI predicts a splice effect with a max delta score of 1.00, but the MSH6 VCEP PP3 splice rule is limited to non-canonical splicing nucleotides, and the PVS1 framework for canonical ±1/2 splice variants states that PP3 should not be combined for the same splice-prediction evidence. A BayesDel score of 0.325996 is available but is not the operative VCEP rule for this canonical splice-donor variant.
spliceai bayesdel cspec pvs1_variant_assessment
PM6 N/A PM6 is not used in the MSH6 VCEP framework.
cspec
PM1 N/A PM1 is not used in the MSH6 VCEP framework.
cspec
PM3 Not assessed No data were identified showing this variant in trans with another MSH6 pathogenic or likely pathogenic variant in a proband meeting the VCEP PM3 framework, so PM3 was not applied.
cspec vcep_table_for_cmmrd_diagnosis
BS4 Not assessed No non-segregation data were identified for this variant, so BS4 cannot be applied.
cspec
PM5 N/A PM5 is a missense-residue rule and is not applicable to this splice-donor variant.
cspec
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