Variant classification summary

NM_000179.3:c.3162C>T

MSH6 · NP_000170.1:p.(Ile1054=) · NM_000179.3

GRCh37: chr2:48028284 C>T · GRCh38: chr2:47801145 C>T

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BS1 strong benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ile1054=)

gnomAD AF

4.905516035448873e-05 (v4.1)

ClinVar

Benign/Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.3:c.3162C>T (p.Ile1054=) is a synonymous variant in exon 4 of MSH6 with a gnomAD v4.1 grpmax filtering allele frequency of 0.059% (79/1,610,432 alleles), meeting VCEP BS1 at Strong strength.

2

SpliceAI predicts no splicing impact for this synonymous variant (max delta score 0.03), meeting VCEP BP4 at Supporting strength.

3

The variant is synonymous and located beyond the splice consensus region in exon 4, meeting VCEP BP7 at Supporting strength.

4

ClinVar classifies this variant as Benign/Likely benign (Variation ID 184018, review status: criteria provided, multiple submitters, no conflicts).

5

No pathogenic criteria are met for this variant. Under VCEP InSiGHT MMR v2.0.0 classification rules, one Benign Strong criterion (BS1) plus one or more Benign Supporting criteria (BP4, BP7) yields a classification of Likely Benign (Rule 18).

Final determination: Rule19 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	Synonymous variant NP_000170.1:p.(Ile1054=) does not introduce a premature termination codon, affect canonical splice sites, or alter the reading frame. PVS1 is not applicable to silent substitutions under either VCEP MMR or generic ACMG/AMP PVS1 frameworks.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Synonymous variant p.(Ile1054=) does not encode an amino acid change. PS1 requires a missense substitution producing the same amino acid change as a known pathogenic variant.
PS2	Not met	No de novo observations identified in ClinVar submissions, published literature, or other evidence sources for NM_000179.3:c.3162C>T.	clinvar
PS3	Not met	No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation spreadsheet or in the published literature. This synonymous variant has not been assessed in MMR functional assays.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
PS5	N/A	PS5 is not included as an active criterion in the InSiGHT MMR VCEP v2.0.0 framework, and no variant-specific case-control or statistical evidence for this synonymous variant exists.	cspec
PM1	N/A	PM1 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
PM2	Not met	PM2_Supporting threshold under the VCEP requires absence or extreme rarity with gnomAD v4 allele frequency below 0.00002 (<1 in 50,000 alleles). This variant has a gnomAD v4.1 allele frequency of 0.000049 (79/1,610,432 alleles), which exceeds the PM2 threshold.	gnomad_v4 cspec
PM5	N/A	Synonymous variant p.(Ile1054=) produces no amino acid change. PM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic.	pm5_candidates
PM6	N/A	PM6 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
PP1	Not met	No co-segregation data available in published literature or ClinVar submissions for NM_000179.3:c.3162C>T.	clinvar
PP2	N/A	PP2 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
PP3	Not met	Synonymous variant; VCEP PP3 rules for missense variants require HCI prior >0.68, which is not applicable (synonymous changes are not in the HCI missense prior table). The synonymous/intronic splice prediction rule requires SpliceAI delta >= 0.2; this variant has a max SpliceAI delta of 0.03, well below the threshold.	spliceai vcep_hci_priors_msh6 cspec
PP4	Not met	No tumor MSI or immunohistochemistry data available for this variant. VCEP PP4 requires MSI-H tumor findings and/or loss of MMR protein expression consistent with variant location.	cspec
PP5	N/A	PP5 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
BA1	Not met	VCEP BA1 threshold requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%). The grpmax FAF for this variant is 0.00058972 (0.059%), which does not meet the BA1 threshold.	gnomad_v4 cspec
BS1	Met	gnomAD v4.1 grpmax filtering allele frequency is 0.00058972 (0.059%), which falls within the VCEP BS1 range of ≥ 0.00022 (0.022%) and < 0.0022 (0.22%). This allele frequency is inconsistent with a fully penetrant dominant disorder, meeting BS1 at Strong strength.	gnomad_v4 cspec
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features. BS2 requires confirmation of phase through parental or offspring testing.	cspec
BS3	Not met	No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation. BS3 requires calibrated functional assays with functional odds for pathogenicity ≤ 0.05 (Strong) or >0.05 & ≤0.48 (Supporting), or variant-specific proficient function in MMR laboratory assays.	vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No segregation or lack-of-segregation data available for NM_000179.3:c.3162C>T. BS4 requires a combined Bayes Likelihood Ratio < 0.05 (Strong) or > 0.05 & ≤ 0.48 (Supporting) from pedigree analysis.	cspec
BP1	N/A	BP1 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
BP2	N/A	BP2 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0.	cspec
BP4	Met	Synonymous variant with SpliceAI max delta score of 0.03, which is ≤ 0.1. Under VCEP BP4 rules, synonymous variants with SpliceAI delta ≤ 0.1 meet BP4_Supporting as they are predicted to have no splicing impact.	spliceai cspec
BP5	Not met	No tumor data available to assess MSS status or MMR protein expression. VCEP BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation findings.	cspec
BP6	N/A	BP6 is designated Not Applicable by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP for MSH6 Version 2.0.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Met	NM_000179.3:c.3162C>T is a synonymous variant in exon 4, located 10 bases upstream of the 3' exon boundary (c.3172), which satisfies the VCEP BP7 requirement of being at or beyond +7 from the 3' splice site. SpliceAI predicts no splicing impact (delta 0.03), supporting no effect on splicing.	spliceai cspec

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