Variant classification summary

NM_000251.3:c.1132del

MSH2 · NP_000242.1:p.(Glu378LysfsTer34) · NM_000251.3

GRCh37: chr2:47656935 AG>A · GRCh38: chr2:47429796 AG>A

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.(Glu378LysfsTer34)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000251.3:c.1132del is a frameshift deletion in exon 7 of MSH2 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), satisfying PVS1_VeryStrong per the InSiGHT MMR VCEP (PTC ≤ codon 891).

2

The variant is absent from gnomAD v4.1, satisfying PM2_Supporting per InSiGHT VCEP (allele frequency <0.00002).

3

No other pathogenic or benign criteria are met. The variant is absent from ClinVar; no tumor pathology, functional assay, segregation, or de novo data are available. The five publications reviewed are gene-level reviews that do not mention NM_000251.3:c.1132del.

4

Under the InSiGHT MMR VCEP combining rules, PVS1_VeryStrong requires at least 1 Strong, 2 Moderate, 1 Moderate + 1 Supporting, or 2 Supporting criteria in combination to reach Pathogenic; or 1 Moderate to reach Likely Pathogenic. With only PM2_Supporting in addition to PVS1_VeryStrong, none of these thresholds are met.

5

This variant is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MMR VCEP framework: 1 × PVS1_VeryStrong + 1 × PM2_Supporting does not satisfy any Pathogenic or Likely Pathogenic combining rule.

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.1132del is a frameshift deletion in exon 7 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), well below the codon 891 threshold specified by the InSiGHT MMR VCEP for PVS1_VeryStrong in MSH2.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 applies to missense variants encoding the same amino acid change as a known pathogenic variant, or to splice-site variants; NM_000251.3:c.1132del is a frameshift deletion.
PS2	Not met	No de novo observations for NM_000251.3:c.1132del were identified in ClinVar, the literature, or any reviewed source.
PS3	Not met	The InSiGHT VCEP PS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no validated functional assay data exist for frameshift variants such as c.1132del.	vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	The InSiGHT MMR VCEP does not utilize PS4 for classification; tumor IHC data are captured under PP4 instead.
PS5	N/A	PS5 is not part of the InSiGHT MMR VCEP framework (criteria set: PP4, BP3, BP7, BS4, BS3, PM5, BP2, PM2, BP4, BP6, PS1, PS2, BS1, PM1, PP5, PP1, BP5, PM6, BA1, PVS1, PS4, PM4, PS3, PP3, BS2, BP1, PP2).
PM1	N/A	The InSiGHT VCEP states there are no recognized mutational hotspots for classification purposes in MMR genes; PM1 is not applicable in this framework.	cspec
PM2	Met	NM_000251.3:c.1132del is absent from gnomAD v4.1, satisfying the InSiGHT VCEP PM2_Supporting criterion (allele frequency <0.00002, i.e., <1 in 50,000 alleles).	gnomad_v4
PM4	N/A	The InSiGHT MMR VCEP does not utilize PM4.
PM5	N/A	PM5 applies only to missense variants at an amino acid residue where a different missense change is classified as pathogenic; NM_000251.3:c.1132del is a frameshift deletion, not a missense variant.
PM6	N/A	The InSiGHT MMR VCEP does not utilize PM6.
PP1	Not met	No co-segregation data are available for NM_000251.3:c.1132del in any reviewed source.
PP2	N/A	The InSiGHT MMR VCEP does not utilize PP2.
PP3	Not met	No in silico evidence supports pathogenicity for this frameshift variant. SpliceAI max delta score is 0.09, which falls below the VCEP PP3 threshold of ≥0.2 for non-canonical splice predictions. HCI prior is not applicable to deletion variants.	spliceai
PP4	Not met	No tumor MSI or IHC data are available for NM_000251.3:c.1132del to satisfy the InSiGHT VCEP PP4 criterion (≥1 CRC/endometrial MSI-H tumor with consistent MMR protein loss).
PP5	N/A	The InSiGHT MMR VCEP does not utilize PP5, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the BA1 threshold (≥0.1% Grpmax FAF).	gnomad_v4
BS1	Not met	NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the InSiGHT VCEP BS1 threshold (≥0.01% and <0.1% Grpmax FAF, excluding founder variants).	gnomad_v4
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic MSH2 variant was identified in any reviewed source.
BS3	Not met	The InSiGHT VCEP BS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no functional data demonstrating normal protein function exist for this frameshift variant.	vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease for NM_000251.3:c.1132del.
BP1	N/A	The InSiGHT MMR VCEP does not utilize BP1.
BP2	N/A	The InSiGHT MMR VCEP does not utilize BP2; BS2 is used instead.
BP3	N/A	The InSiGHT VCEP states BP3 is not applicable; it applies to in-frame deletions/insertions in repetitive regions without known function, which does not describe this frameshift deletion.
BP4	N/A	The InSiGHT VCEP BP4 rules apply only to missense variants (HCI prior <0.11) and intronic/synonymous variants (SpliceAI delta ≤0.1). NM_000251.3:c.1132del is a frameshift deletion; neither computational evidence pathway is applicable.
BP5	Not met	No tumor data are available to demonstrate microsatellite stability, intact MMR protein expression, or an alternative molecular basis (e.g., BRAF V600E, MLH1 methylation) for tumors harboring NM_000251.3:c.1132del.
BP6	N/A	The InSiGHT MMR VCEP does not utilize BP6, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	N/A	The InSiGHT VCEP BP7 rule applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000251.3:c.1132del is a frameshift deletion.
PM3	N/A	Skipped by instruction; PM3 was flagged as trivially not applicable.

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