Variant classification summary

NM_000179.3:c.2294G>C

MSH6 · NP_000170.1:p.(Cys765Ser) · NM_000179.3

GRCh37: chr2:48027416 G>C · GRCh38: chr2:47800277 G>C

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Cys765Ser)

gnomAD AF

6.195364628185191e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: the variant is extremely rare in gnomAD v4.1, with an allele frequency of 6.20e-07 and zero homozygotes.

Final determination: Under the ClinGen InSiGHT MSH6 Version 2.0 framework, PM2 Supporting alone does not satisfy any pathogenic or benign combination rule, so the classification remains 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	N/A	Not applicable: c.2294G>C is a missense change producing p.(Cys765Ser), not a VCEP-defined nonsense, frameshift, splice, or large-alteration loss-of-function variant.	cspec
PS1	Not assessed	Not assessed: no validated VCEP-Pathogenic alternate-nucleotide comparator for p.Cys765Ser was identified, but the comparator search had a retrieval failure.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no proband-level parental testing or de novo evidence is documented for assigning the VCEP's 0.5–2 points per proband.	cspec
PS3	Not assessed	Not assessed: no variant-specific calibrated functional assay result, functional-odds estimate, or demonstrated MMR defect is available for p.Cys765Ser.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the MSH6 InSiGHT Version 2.0 specification explicitly designates PS4 as Not Applicable.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP explicitly designates PM1 as Not Applicable for this gene.	cspec
PM2	Met	Met at Supporting: gnomAD v4.1 total AF 6.20e-07 is below the VCEP PM2 threshold of 0.00002, with zero homozygotes.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or confirmed phase with a pathogenic MSH6 variant is documented to assign any PM3 points.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP explicitly excludes PM4, and c.2294G>C is a missense substitution without a protein-length change.	cspec
PM5	Not assessed	Not assessed: zero same-residue comparator candidates were collected, but the search recorded an HTTP 429 retrieval failure.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 InSiGHT VCEP explicitly designates PM6 as not applicable and routes assumed de novo cases through PS2.	cspec
PP1	Not assessed	Not assessed: no informative affected-relative meioses or combined Bayes likelihood ratio is documented against the VCEP's 2.08 supporting threshold.	cspec
PP2	N/A	Not applicable: the MSH6 VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: governing MSH6 HCI prior probability is 0.4345, below the PP3 supporting threshold of >0.68.	cspec vcep_hci_priors_msh6 hci_prior
PP4	Not assessed	Not assessed: no patient-specific MSI, tumor-genome, MMR-protein-loss, or qualifying-tumor-count evidence is available for PP4.	cspec
PP5	N/A	Not applicable: the MSH6 specification excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum observed population frequency 8.47e-07 is far below the VCEP BA1 threshold of 0.0022.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 maximum observed population frequency 8.47e-07 is below the VCEP BS1 lower threshold of 0.00022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying VCEP-defined in-trans co-occurrence and confirmed phase evidence are available for BS2.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient functional assay result or calibrated functional odds value <=0.48 is available for p.Cys765Ser.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no informative non-segregation data or combined Bayes likelihood ratio is documented against the VCEP's 0.48 upper threshold.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the MSH6 Version 2.0 VCEP specification explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP explicitly excludes BP3, and c.2294G>C is missense rather than a repeat-region in-frame indel.	cspec
BP4	Not met	Not met: governing MSH6 HCI prior probability is 0.4345, above the BP4 supporting threshold of <0.11.	cspec vcep_hci_priors_msh6 hci_prior
BP5	Not assessed	Not assessed: no qualifying MSS, MMR-expression, BRAF V600E, MLH1-methylation, or tumor-count evidence is available for BP5.	cspec
BP6	N/A	Not applicable: the MSH6 specification excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.2294G>C causes the missense substitution p.Cys765Ser, not a synonymous or qualifying intronic change.	cspec

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