Variant classification summary

NM_000251.3:c.712del

MSH2 · NP_000242.1:p.(Tyr238IlefsTer8) · NM_000251.3

GRCh37: chr2:47639616 AT>A · GRCh38: chr2:47412477 AT>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.(Tyr238IlefsTer8)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift introduces a premature stop at codon 245, triggering nonsense-mediated decay.

2

PM2 (Supporting): variant absent from gnomAD v4.1, below the 1-in-50,000 allele-frequency threshold.

3

Overall: VUS - one Very Strong plus one Supporting matches no combining rule under the InSiGHT MSH2 framework.

Final determination: No InSiGHT MSH2 CSPEC v2.0 rule fires on PVS1(VeryStrong)+PM2(Supporting) alone; defaults to VUS.

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	Met (Very Strong): frameshift introduces a premature stop at codon 245, before the VCEP threshold of codon 891, predicting nonsense-mediated decay.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: this is a frameshift deletion, not a missense or splice-site change, so the same-amino-acid comparison cannot apply.	cspec
PS2	Not assessed	Not assessed: no de novo observation with parental testing or phenotype information was available.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result (e.g., MMR activity or mRNA stability) was available.
PS4	N/A	Not applicable: tumor IHC evidence is evaluated through PP4 under this gene's framework, not proband counting.	cspec
PM1	N/A	Not applicable: this gene's expert framework designates PM1 as not applicable for MSH2.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1, below the 1-in-50,000 allele-frequency threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no observation of the variant with a second MSH2 variant or phase testing was available.	cspec
PM4	N/A	Not applicable: already fully scored under PVS1 as a truncating frameshift, not an in-frame length change.	cspec
PM5	N/A	Not applicable: this is a frameshift deletion, not a missense change, so residue-level missense comparison does not apply.	cspec
PM6	N/A	Not applicable: unconfirmed de novo observations are not evaluated for this gene under its expert framework.	cspec
PP1	Not assessed	Not assessed: no pedigree or relative genotype data was available for co-segregation analysis.	cspec
PP2	N/A	Not applicable: this gene's expert framework excludes PP2, and the variant is a frameshift, not missense.	cspec
PP3	N/A	Not applicable: PP3 covers missense or splice-site variants; this frameshift's impact is assessed under PVS1.	cspec
PP4	Not assessed	Not assessed: no tumor MSI or MMR immunohistochemistry result was provided.	cspec
PP5	N/A	Not applicable: no expert-panel assertion exists in ClinVar for this exact variant.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v4.1, far below the >=0.001 population frequency threshold.	cspec gnomad_v4
BS1	Not met	Not met: absent from gnomAD v4.1, below the 0.0001-0.001 population frequency interval.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no evidence of the variant in trans with a known pathogenic MSH2 variant was available.	cspec
BS3	Not assessed	Not assessed: no calibrated functional assay result showing proficient MSH2 function was available.
BS4	Not assessed	Not assessed: no informative non-segregation or pedigree observations were available.	cspec
BP1	N/A	Not applicable: this gene's framework excludes BP1, and the variant is truncating, not missense.	cspec
BP2	N/A	Not applicable: this gene's expert framework explicitly excludes BP2.	cspec
BP3	N/A	Not applicable: BP3 covers in-frame indels; this is a frameshift deletion.	cspec
BP4	N/A	Not applicable: BP4 covers only missense or intronic/synonymous variants; this is a frameshift deletion.	cspec spliceai
BP5	Not assessed	Not assessed: no tumor MSS, IHC, BRAF V600E, or MLH1 methylation evidence was provided.	cspec
BP6	N/A	Not applicable: no expert-panel benign assertion exists in ClinVar for this exact variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or intronic variants; this is a coding frameshift deletion.	cspec

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