Variant classification summary

NM_000179.3:c.914C>A

MSH6 · NP_000170.1:p.(Thr305Asn) · NM_000179.3

GRCh37: chr2:48026036 C>A · GRCh38: chr2:47798897 C>A

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Thr305Asn)

gnomAD AF

6.195203425699686e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: the gnomAD v4.1 allele frequency is 6.1952e-07, below the VCEP cutoff of 0.00002.

2

BP4 Supporting: the HCI prior pathogenicity probability is 0.0264, below the VCEP cutoff of 0.11.

Final determination: Under the MSH6 VCEP Version 2.0 criteria-combination rules, PM2 Supporting plus BP4 Supporting satisfies neither a pathogenic nor a benign rule, so the final call is 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.914C>A is missense p.Thr305Asn, not one of the VCEP PVS1 rule's qualifying null, splice, duplication, or initiation-codon variants.	cspec
PS1	Not met	Not met: no different-nucleotide p.Thr305Asn variant previously established as Pathogenic by this VCEP was identified; the only exact row was c.914C>A itself.	cspec vcep_hci_priors_msh6
PS2	Not assessed	Not assessed: no documented de novo event, parental testing, or VCEP de novo point assignment is available for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional result or functional odds were available for c.914C>A/p.T305N, so the calibrated PS3 threshold (>2.08) cannot be evaluated.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the MSH6 VCEP explicitly marks PS4 as Not Applicable.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP explicitly excludes PM1 because hotspots are unrecognized and pathogenic variants are generalized across functional domains.	cspec vcep_mmr_functional_domains
PM2	Met	Met, Supporting: gnomAD v4.1 total AF is 6.1952e-07, below the VCEP threshold of <0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no documented CMMRD proband, second pathogenic/likely pathogenic MSH6 variant, or confirmed phase supports assigning PM3 points.	cspec
PM4	N/A	Not applicable: p.(Thr305Asn) is a missense substitution with no protein-length change, whereas the VCEP PM4 instruction addresses in-frame length changes.	cspec
PM5	Not met	Not met: zero same-residue PM5 candidates were identified, so no VCEP-classified Pathogenic or Likely Pathogenic alternate missense comparator is available.	cspec pm5_candidates vcep_hci_priors_msh6
PM6	N/A	Not applicable: the MSH6 VCEP specification explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree segregation data or combined Bayes likelihood ratio is reported for this variant.	cspec
PP2	N/A	Not applicable: the MSH6 VCEP explicitly marks PP2 not applicable for missense variants in this gene framework.	cspec
PP3	Not met	Not met: HCI prior pathogenicity probability is 0.0264, below the VCEP PP3_Supporting threshold of >0.68.	cspec vcep_hci_priors_msh6
PP4	Not assessed	Not assessed: no qualifying CRC/endometrial MSI-H tumor or MSH6 protein-expression evidence is available for the VCEP PP4 rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MSH6 VCEP explicitly marks PP5 as Not Applicable.	cspec
BA1	Not assessed	Not assessed: the required gnomAD v4 Grpmax filtering allele frequency is unavailable, despite a reported highest observed population AF of 1.09794e-05.	cspec gnomad_v4
BS1	Not assessed	Not assessed: the required gnomAD v4 Grpmax filtering allele frequency is unavailable, while the reported highest observed population AF is 1.09794e-05.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, cancer-age, CMMRD, and phase-confirmation evidence is available for the BS2 rule.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific proficient-function result or functional odds were available for c.914C>A/p.T305N, so the calibrated BS3 threshold (<=0.48) cannot be evaluated.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregation observations or combined Bayes likelihood ratio is available for this variant.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP explicitly marks BP1 not applicable for missense variants in this gene framework.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP marks BP2 not applicable and directs evaluators to use BS2 instead.	cspec
BP3	N/A	Not applicable: p.(Thr305Asn) is missense, not an in-frame deletion or insertion in a repetitive region without known function.	cspec
BP4	Met	Met at Supporting: HCI prior pathogenicity probability is 0.0264, below the VCEP BP4 threshold of <0.11.	cspec vcep_hci_priors_msh6
BP5	Not assessed	Not assessed: no qualifying MSS/no-loss tumor count or BRAF V600E/MLH1-methylation finding is available for BP5.	cspec
BP6	N/A	Not applicable: the MSH6 VCEP explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: p.(Thr305Asn) is a missense variant, whereas VCEP BP7 covers only synonymous or intronic variants.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.