Variant classification summary

NM_000179.3:c.2463A>C

MSH6 · NP_000170.1:p.(Leu821=) · NM_000179.3

GRCh37: chr2:48027585 A>C · GRCh38: chr2:47800446 A>C

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Leu821=)

gnomAD AF

6.1959327419109e-07 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI predicts no splicing impact (max delta 0.001, below the 0.1 threshold) for this synonymous variant.

2

BP7 (Supporting): synonymous variant deep within the exon interior (1835 bp from the 5' splice boundary), with SpliceAI max delta 0.001 confirming no splice impact.

3

Overall: Likely Benign, per InSiGHT MSH6 VCEP v2.0 Rule19 (>=2 Benign.Supporting criteria).

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 synonymous variant (p.Leu821=) is not a truncating or canonical splice-site change covered by the PVS1 rule.	cspec spliceai
PS1	N/A	Not applicable: the variant makes no amino acid change, leaving nothing to compare against known pathogenic variants.	cspec spliceai
PS2	Not assessed	Not assessed: no de novo or parental-testing data were available.	cspec
PS3	Not assessed	Not assessed: no functional assay or mRNA-based study results were available for this variant.
PS4	N/A	Not applicable: the MSH6 VCEP routes tumor immunohistochemistry evidence through PP4, not PS4.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP defines no mutational hotspot, and this synonymous variant changes no amino acid.	cspec spliceai
PM2	Not met	Not met: the highest ancestry-specific frequency (3.38e-05 in Ashkenazi Jewish) exceeds the <0.00002 cutoff despite a 6.20e-07 total frequency. Flagged for human review: this rests on a single allele, and Grpmax FAF was unavailable.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no co-occurring pathogenic MSH6 variant or CMMRD-consistent phenotype data were available.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP marks PM4 not applicable, and the variant does not alter protein length.	cspec
PM5	N/A	Not applicable: the variant is synonymous, so there is no amino acid change to compare at codon 821.	cspec pm5_candidates
PM6	N/A	Not applicable: designated not applicable by the MSH6 InSiGHT VCEP specification.	cspec
PP1	Not assessed	Not assessed: no segregation or pedigree genotype/phenotype data were available.	cspec
PP2	N/A	Not applicable: the MSH6 VCEP marks PP2 not applicable, and the variant is not missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.001, far below the 0.2 PP3 threshold; the variant is also not missense.	cspec spliceai
PP4	Not assessed	Not assessed: no tumor MSI or MMR immunohistochemistry results were available.	cspec
PP5	N/A	Not applicable: the MSH6 VCEP designates PP5 not applicable, with no expert-panel submission on record.	cspec clinvar
BA1	Not met	Not met: highest ancestry-specific allele frequency 3.38e-05, far below the 0.0022 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: highest ancestry-specific allele frequency 3.38e-05, more than six-fold below the 0.00022 lower bound.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no in-trans co-occurrence with a pathogenic MSH6 variant in an eligible patient was documented.	cspec
BS3	Not assessed	Not assessed: no NMD-inhibition mRNA assay or calibrated functional assay result was available.
BS4	Not assessed	Not assessed: no non-segregation observations or likelihood ratio data were available.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP marks BP1 not applicable, and the variant is not missense.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP directs use of BS2 instead of BP2.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP marks BP3 not applicable; the change is also a single-nucleotide substitution, not an in-frame indel.	cspec
BP4	Met	Met (supporting): SpliceAI max delta 0.001, well below the <=0.1 threshold indicating no splicing impact.	cspec spliceai
BP5	Not assessed	Not assessed: no tumor MSS, MMR IHC, BRAF V600E, or MLH1 methylation results were available.	cspec
BP6	N/A	Not applicable: the MSH6 VCEP designates BP6 not applicable, with no expert-panel benign assertion on record.	cspec clinvar
BP7	Met	Met (supporting): synonymous variant deep in the exon interior (1835 bp from the 5' splice boundary) with SpliceAI max delta 0.001.	cspec spliceai

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