NM_000251.3:c.609del

MSH2 · NP_000242.1:p.(Gly204GlufsTer10) · NM_000251.3

GRCh37: chr2:47637474 GA>G · GRCh38: chr2:47410335 GA>G

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Gly204GlufsTer10)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000251.3:c.609del (p.Gly204GlufsTer10) is a frameshift deletion in exon 3 of MSH2 that introduces a premature termination codon at position 214, well before the InSiGHT VCEP-defined cutoff of codon 891 for PVS1 application at Very Strong strength.

The variant is absent from population databases including gnomAD v2.1 and v4.1 (0 alleles across all populations), meeting the VCEP PM2_Supporting threshold of <1 in 50,000 alleles.

SpliceAI predicts no splice-altering effect (max delta score = 0.01), consistent with a frameshift deletion that exerts its effect at the protein level through premature truncation rather than aberrant splicing.

OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating mechanism.

No benign evidence criteria (BA1, BS1, BS2, BS3, BS4, BP5) are met; the variant is absent from population databases, no functional data support benign effect, and no alternate molecular basis or negative segregation data exist.

Applying the InSiGHT MSH2 VCEP v2.0.0 combining rules: PVS1_VeryStrong + PM2_Supporting yields 1 Very Strong + 1 Supporting. The VCEP rule set does not define a specific rule for this exact combination (Rule 4 requires ≥2 Supporting for Pathogenic; Rule 10 requires 1 Moderate for LP). Falling back to generic ACMG/AMP 2015 combination rules (PMID:25741868): 1 PVS1-level evidence (minimum Strong equivalent) + 1 Supporting → Likely Pathogenic. PP1 and PP4 remain unassessed; if either is met at Supporting level, the classification would upgrade to Pathogenic under VCEP Rule 4.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules 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	Met	NM_000251.3:c.609del is a frameshift deletion introducing a premature termination codon at codon 214 (p.Gly204GlufsTer10), well before the VCEP-defined cutoff of codon 891 in MSH2. The variant resides in exon 3 of 16 and is predicted to undergo nonsense-mediated decay. Under the InSiGHT MMR VCEP PVS1 decision tree, frameshift variants introducing a PTC at or before codon 891 meet PVS1 at Very Strong strength.	cspec gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies to missense substitutions encoding the same amino acid change as a known pathogenic variant, or to variants affecting the same non-canonical splice nucleotide. c.609del is a frameshift deletion, not a missense substitution or splice variant.
PS2	Not met	No de novo occurrence has been reported for NM_000251.3:c.609del in any available database or publication. Exploratory literature and database searches found no evidence of confirmed de novo status with maternity and paternity confirmation.
PS3	N/A	The VCEP functional assay documentation (Functional-assay-SVI-documentation-MMR.xlsx) is targeted to missense, splice site, and synonymous variants. c.609del is a frameshift truncating variant whose pathogenic mechanism (loss of function via premature termination and NMD) is already captured by PVS1. Calibrated functional assays in the MMR VCEP framework are not designed or validated for frameshift null variants.
PS4	N/A	PS4 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification.	cspec
PS5	N/A	PS5 is not defined in the InSiGHT MSH2 VCEP v2.0.0 criteria specification.	cspec
PM1	N/A	The InSiGHT MSH2 VCEP v2.0.0 explicitly excludes PM1: '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.'	cspec
PM2	Met	NM_000251.3:c.609del is absent from gnomAD v2.1 (0 alleles) and gnomAD v4.1 (0 alleles). This satisfies the InSiGHT MSH2 VCEP PM2_Supporting rule requiring an allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a second pathogenic variant. MSH2 Lynch syndrome is autosomal dominant; PM3 is not applicable to this inheritance pattern. No biallelic CMMRD reports with this variant were identified.
PM4	N/A	PM4 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Protein-length changes due to frameshift are captured by PVS1 in this framework.	cspec
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic. c.609del is a frameshift deletion, not a missense variant. PM5 candidate search confirmed ineligibility.
PM6	N/A	PM6 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification.	cspec
PP1	Not assessed	Co-segregation data was not available for adjudication. The exploratory search identified a possible Finnish founder study (PMID 9230861) and InSiGHT database annotations suggesting segregation with Lynch syndrome, but no full-text or database segregation statistics were accessible to calculate a Bayes Likelihood Ratio under the VCEP PP1 rule.
PP2	N/A	PP2 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification.	cspec
PP3	N/A	PP3 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior >0.68 (for Supporting) or a non-canonical splice variant with SpliceAI delta ≥0.2. c.609del is a frameshift deletion, not a missense substitution. SpliceAI predicts no splice impact (max delta = 0.01). HCI prior lookup is not applicable to deletions.	spliceai cspec
PP4	Not assessed	No tumor phenotype data (MSI status, IHC for MMR proteins) was available for this case. Under the InSiGHT VCEP, PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Without tumor data, PP4 cannot be evaluated.
PP5	N/A	PP5 is marked as Not Applicable for this VCEP by the InSiGHT MSH2 specification. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Not met	BA1 under the InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%). NM_000251.3:c.609del is absent from gnomAD v4.1 (AF = 0), so BA1 is not met.	gnomad_v4
BS1	Not met	BS1 under the InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%). The variant is absent from gnomAD v4.1, so BS1 is not met.	gnomad_v4
BS2	Not met	No evidence of this variant observed in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 without CMMRD features. BS2 requires confirmed phase and specific clinical context not available for this case.
BS3	N/A	The VCEP functional assay documentation covers missense, splice site, and synonymous variants. BS3 requires calibrated functional assays showing no damaging effect. For a frameshift truncating variant like c.609del, the pathogenic mechanism (premature termination, NMD) is inherently damaging; calibrated functional assays in the MMR framework are not designed for null variants. The VCEP functional assay flowchart addresses residue-level function, not truncation-based loss of function.
BS4	Not met	No evidence of lack of co-segregation with disease has been reported for NM_000251.3:c.609del. BS4 requires a combined Bayes Likelihood Ratio showing no segregation, which is not available. Given the variant's association with Lynch syndrome, BS4 is unlikely to be met.
BP1	N/A	BP1 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification.	cspec
BP2	N/A	BP2 is marked as Not Applicable by the InSiGHT MSH2 VCEP. The VCEP uses BS2 instead for co-occurrence evidence.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. c.609del is a frameshift (not in-frame) deletion, so BP3 is not applicable.	cspec
BP4	N/A	BP4 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior <0.11 or an intronic/synonymous variant with SpliceAI delta ≤0.1. c.609del is a frameshift coding deletion — neither a missense nor an intronic/synonymous variant. HCI prior is not computed for deletions.	cspec spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease (e.g., BRAF V600E, MLH1 methylation, or MSS tumors inconsistent with MSH2 involvement). BP5 requires tumor data not available for this case.
BP6	N/A	BP6 is marked as Not Applicable for this VCEP by the InSiGHT MSH2 specification. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). c.609del is a coding frameshift deletion, not a synonymous or intronic variant.	cspec

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