Variant classification summary

NM_000251.2:c.1511-1G>A

MSH2 · NP_000242.1:p.? · NM_000251.2

GRCh37: chr2:47693796 G>A · GRCh38: chr2:47466657 G>A

Gene: MSH2 Transcript: NM_000251.2

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.2

Protein

NP_000242.1:p.?

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000251.2:c.1511-1G>A is a canonical splice acceptor variant (IVS9-1G>A) in MSH2, absent from gnomAD population databases.

2

PVS1 (very strong) is applied per the InSiGHT MMR VCEP v2.0 decision tree: variants at IVS±1 or IVS±2 where exon skipping disrupts reading frame and is predicted to undergo NMD. SpliceAI predicts strong acceptor loss (delta 0.99).

3

PM2 (supporting) is applied per InSiGHT VCEP: variant is absent from gnomAD v4.1, meeting the allele frequency threshold of <0.00002 (<1 in 50,000 alleles).

4

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and Likely Pathogenic (2 clinical laboratories); however, PP5 is not applied per VCEP 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 MSH2 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	Met	NM_000251.2:c.1511-1G>A is a canonical splice acceptor variant (IVS9-1G>A) in MSH2. Under the InSiGHT MMR VCEP v2.0 PVS1 decision tree, variants at IVS±1 or IVS±2 where exon skipping disrupts reading frame and is predicted to undergo NMD are assigned PVS1 (very strong). Loss of function is an established disease mechanism for MSH2. SpliceAI predicts strong splicing impact (max delta score 0.99, acceptor loss 0.99). Not combined with PP3 per VCEP rule.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Variant is a canonical splice site change, not a missense substitution; no other Pathogenic variant has been established at this same splice nucleotide by the VCEP.
PS2	Not met	No de novo observation data available for this variant in any reviewed publication or database.
PS3	Not met	No calibrated functional assay data or variant-specific experimental evidence is available for NM_000251.2:c.1511-1G>A. The VCEP MMR functional assay documentation covers calibrated assays for missense variants but no functional study has tested this specific splice variant. SpliceAI prediction alone is in silico evidence, not functional data.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification.
PS5	N/A	PS5 is not defined in the InSiGHT MMR VCEP v2.0 specification; variant is a canonical splice site change, not a missense substitution at an amino acid residue.
PM1	N/A	PM1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0. Per VCEP instructions: 'There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains.'
PM2	Met	This variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, meeting the InSiGHT VCEP allele frequency threshold of <0.00002 (<1 in 50,000 alleles).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic/Likely Pathogenic. This variant is a canonical splice site change, not a missense. pm5_candidates.json confirms not_applicable.
PM6	N/A	PM6 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification.
PP1	Not met	No co-segregation data available for this variant in any reviewed family or pedigree.
PP2	N/A	PP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification.
PP3	N/A	Under the InSiGHT MMR VCEP v2.0, PP3 for splice variants applies only to non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2. This variant (c.1511-1G>A) is a canonical IVS±1,2 splice site change. Additionally, the PVS1 rule explicitly states: 'Not to be combined with PP3.' Not a missense variant, so HCI prior PP3 does not apply.
PP4	Not met	No tumor MSI/IHC data specific to this variant is available. The ClinVar submissions (Variation ID 619529) report classifications of Pathogenic (2 labs) and Likely Pathogenic (2 labs) but do not provide patient-level tumor phenotype data for review.	clinvar
PP5	N/A	PP5 is designated Not Applicable for this VCEP by the InSiGHT MMR VCEP v2.0 specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar review status is 'criteria provided, single submitter' (1-star), which would not meet the 3-star threshold for PP5 under generic rules.
BA1	Not met	This variant is absent from gnomAD v4.1 (0 alleles). The InSiGHT VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met.	gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1. The InSiGHT VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), which is not met.	gnomad_v4
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 without CMMRD features, as required by the InSiGHT VCEP BS2 rule.
BS3	Not met	No variant-specific functional data demonstrating proficient function or normal splicing is available. SpliceAI predicts strong splicing impact (max delta 0.99), inconsistent with a benign functional effect. The VCEP functional assay documentation does not include data for this variant.	spliceai vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No co-segregation or lack-of-segregation data available for this variant.
BP1	N/A	BP1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification.
BP2	N/A	BP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification; BS2 is used instead.
BP4	Not met	Under the InSiGHT VCEP, BP4 for intronic variants requires SpliceAI delta score <= 0.1, indicating no splicing impact. This variant has a SpliceAI max delta score of 0.99, far exceeding the benign threshold. Not a missense variant, so HCI prior BP4 does not apply.	spliceai
BP5	Not met	No evidence of MSS tumors or inconsistent MMR protein expression is available for this variant.
BP6	N/A	BP6 is designated Not Applicable for this VCEP by the InSiGHT MMR VCEP v2.0 specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
BP7	Not met	Under the InSiGHT VCEP, BP7 applies to intronic variants at or beyond -21/+7 (5'/3' exonic). This variant is at position c.1511-1 (IVS9-1), which is within the -21/+7 boundary, not beyond it. Additionally, SpliceAI predicts strong splicing impact (delta 0.99), which is inconsistent with a silent intronic variant.	spliceai

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