Variant classification summary

NM_000179.2:c.3926C>A

MSH6 · NP_000170.1:p.(Pro1309Gln) · NM_000179.2

GRCh37: chr2:48033715 C>A · GRCh38: chr2:47806576 C>A

Gene: MSH6 Transcript: NM_000179.2

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

MSH6

Transcript

NM_000179.2

Protein

NP_000170.1:p.(Pro1309Gln)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v4.1 population databases, meeting the VCEP's extreme rarity threshold (<1 in 50,000 alleles).

2

PP3 (Moderate): HCI prior probability of pathogenicity 0.823 exceeds the >0.81 threshold for moderate strength.

3

Overall classification: VUS — PM2 (Supporting) plus PP3 (Moderate) meets no VCEP rule for Pathogenic or Benign.

Final determination:

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: this is a missense change (p.Pro1309Gln), not a nonsense, frameshift, or splice-site variant that would disrupt protein function.	cspec spliceai
PS1	Not assessed	Not assessed: no previously classified pathogenic variant encoding the same p.Pro1309Gln change via an alternate nucleotide was available for comparison.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no de novo observation with parental confirmation was documented for this variant.	cspec
PS3	Not assessed	Not assessed: no functional assay results for this variant (e.g., cell-based mismatch-repair activity) were available.
PS4	N/A	Not applicable: the MSH6 framework does not use PS4, since tumor findings are captured through PP4 instead.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP provides no mutational-hotspot PM1 rule for this gene.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1 population databases, meeting the VCEP's extreme rarity threshold (<1 in 50,000 alleles).	cspec gnomad_v4
PM3	Not assessed	Not assessed: no second pathogenic MSH6 variant or co-occurrence observation was available to evaluate.	cspec
PM4	N/A	Not applicable: this missense change does not alter protein length, and the framework provides no PM4 rule.	cspec
PM5	Not assessed	Not assessed: no previously classified pathogenic variant at residue 1309 could be confirmed for the same-residue comparison.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 VCEP framework does not use PM6.	cspec
PP1	Not assessed	Not assessed: no family segregation data or likelihood ratio was available for this variant.	cspec
PP2	N/A	Not applicable: the MSH6 VCEP does not use PP2, superseding the generic missense-constraint rule.	cspec
PP3	Met	Met (Moderate): HCI prior probability of pathogenicity 0.823 exceeds the >0.81 PP3_Moderate threshold.	cspec hci_prior
PP4	Not assessed	Not assessed: no tumor microsatellite-instability or immunohistochemistry results were available.	cspec
PP5	N/A	Not applicable: the framework does not use PP5, and the ClinVar record lacks an expert-panel submission.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v4.1, below the 0.22% BA1 frequency threshold.	cspec gnomad_v4
BS1	Not met	Not met: absent from gnomAD v4.1, below the 0.022% BS1 frequency threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence with a known pathogenic variant was documented.	cspec
BS3	Not assessed	Not assessed: no functional assay evidence of proficient mismatch-repair function was available for this variant.
BS4	Not assessed	Not assessed: no family data demonstrating lack of segregation was available.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP does not use BP1, superseding the generic missense-mechanism rule.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP framework does not use BP2.	cspec
BP3	N/A	Not applicable: this is a missense change, not an in-frame indel in a repeat region, and the framework provides no BP3 rule.	cspec
BP4	Not met	Not met: HCI prior probability 0.823 is far above the 0.11 BP4 threshold.	cspec hci_prior
BP5	Not assessed	Not assessed: no tumor data establishing an alternate molecular cause (e.g., BRAF V600E or MLH1 methylation) was available.	cspec
BP6	N/A	Not applicable: the framework does not use BP6, and the ClinVar record lacks an expert-panel submission.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or deep intronic variants, and this is a missense change.	cspec

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