Variant classification summary

NM_000179.3:c.1135_1139del

MSH6 · NP_000170.1:p.(Arg379Ter) · NM_000179.3

GRCh37: chr2:48026250 AAAGAG>A · GRCh38: chr2:47799111 AAAGAG>A

Gene: MSH6 Transcript: NM_000179.3

Final call

Pathogenic

PVS1 very strong PS2 supporting PM2 supporting PP4 moderate PP5 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Arg379Ter)

gnomAD AF

2.4780875111823697e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1_Very_Strong: NM_000179.3:c.1135_1139del introduces a premature termination codon at p.Arg379Ter, well within the VCEP boundary of codon 1341. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.

2

PM2_Supporting: This variant is extremely rare in population databases. In gnomAD v4.1, allele frequency is 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), below the VCEP threshold of <0.00002.

3

PP4_Moderate: The variant has been observed in a patient with two independent MSH6-deficient tumors (endometrial cancer at age 54 and colorectal cancer at age 58), meeting VCEP criteria for 2 independent tumors with IHC loss consistent with the variant gene.

4

PS2_Supporting: The variant was identified as a likely de novo mosaic variant detectable across all three germ layers in a patient with MSH6-deficient Lynch spectrum tumors, meeting 0.5 de novo points under the VCEP PS2 scoring system.

5

Combining 1 Very Strong (PVS1) + 2 Supporting (PM2 + PS2) satisfies VCEP Rule 4 (1 VS + >=2 Sup → Pathogenic). The additional Moderate criterion (PP4) further supports the pathogenic classification.

Final determination: Rule4 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 Pathogenic.

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	Met	NM_000179.3:c.1135_1139del is a 5-bp deletion in exon 4 of MSH6 that introduces a premature termination codon at p.Arg379Ter. Under the InSiGHT/ClinGen MSH6 VCEP v2.0.0, nonsense/frameshift variants introducing a PTC at or before codon 1341 meet PVS1 at Very Strong strength. The PTC at codon 379 lies well within this boundary, and loss of function is an established disease mechanism for MSH6 in Lynch syndrome.	pvs1_gene_context pvs1_variant_assessment cspec clinvar
PS1	N/A	PS1 under the MSH6 VCEP applies to missense substitutions encoding the same amino acid change as a previously established Pathogenic/Likely Pathogenic variant, or to splice-site variants affecting the same non-canonical nucleotide. This variant is a frameshift/nonsense variant and does not fall under PS1 applicability.
PS2	Met	PMID 37318702 reports this variant as a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* variant in a patient with MSH6-deficient endometrial and colorectal cancer. The variant was detected at low mosaic levels in blood (1.64%), saliva (3.49%), and normal colonic tissue (5.34%), indicating early embryonic occurrence consistent with de novo origin. Under the MSH6 VCEP PS2 scoring system, a proband with a de novo variant without confirmed parental testing but clinically likely de novo and with MMR-deficient LS spectrum tumors receives 0.5 points, meeting PS2_Supporting.
PS3	Not assessed	No calibrated functional assay data (functional odds for pathogenicity) is available for this specific variant in the VCEP functional assay SVI documentation. OncoKB assigns a Likely Loss-of-function label based on the predicted truncating nature, but this is not empirical functional evidence meeting VCEP PS3 calibrated assay thresholds.	oncokb
PS4	N/A	PS4 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0.	cspec
PS5	N/A	PS5 (reputable source reports variant as pathogenic) is not an applicable criterion under the MSH6 VCEP v2.0.0; the VCEP explicitly makes PP5 and BP6 (which together cover the reputable-source domain) Not Applicable.	cspec
PM1	N/A	PM1 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0.	cspec
PM2	Met	In gnomAD v4.1, this variant has an allele frequency of 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), which is below the VCEP threshold of <0.00002 (<1 in 50,000 alleles). In gnomAD v2.1, it has an AF of 3.98e-06 (1/250,986 alleles). No homozygotes are observed in either dataset. This meets PM2_Supporting per the MSH6 VCEP.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0.	cspec
PM5	N/A	PM5 under the MSH6 VCEP applies to missense changes at an amino acid residue where a different missense change was classified as Pathogenic/Likely Pathogenic. This variant is a frameshift/nonsense variant, not a missense change. The PM5 candidate collection confirms non-eligibility.	pm5_candidates
PM6	N/A	PM6 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0.	cspec
PP1	Not assessed	No co-segregation data (Bayes Likelihood Ratio from pedigrees) is available for this variant in the evidence collected. PP1 requires formal segregation analysis with combined Bayes LR meeting VCEP thresholds (>2.08, >4.3, or >18.7).
PP2	N/A	PP2 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0 (missense variant in gene with low rate of benign missense changes does not apply).	cspec
PP3	Not met	PP3 under the MSH6 VCEP requires either (a) a missense variant with HCI prior probability >0.68, or (b) a non-canonical splice variant with SpliceAI delta score ≥0.2. This variant is not a missense substitution (HCI prior lookup returned no result), and SpliceAI predicts no significant splicing impact (max delta score = 0.03). PP3 is not met.	spliceai
PP4	Met	The case report in PMID 37318702 describes a patient with two independent MSH6-deficient tumors: endometrial cancer at age 54 and colorectal cancer at age 58. Both tumors showed loss of MSH6 protein expression consistent with the variant location. Under the MSH6 VCEP, 2 independent CRC/Endometrial tumors with loss of MMR protein expression consistent with the variant location meets PP4_Moderate.
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	cspec clinvar
BA1	Not met	The MSH6 VCEP BA1 threshold is gnomAD v4 grpmax FAF ≥ 0.0022 (0.22%). This variant has a grpmax FAF of 7.9e-07 (0.000079%), far below the BA1 threshold. BA1 is not met.	gnomad_v4
BS1	Not met	The MSH6 VCEP BS1 threshold is gnomAD v4 grpmax FAF ≥ 0.00022 (0.022%) and < 0.0022. This variant has a grpmax FAF of 7.9e-07 (0.000079%), below the BS1 threshold. BS1 is not met.	gnomad_v4
BS2	Not assessed	BS2 under the MSH6 VCEP requires observation of the variant in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features, with confirmed phase. No such co-occurrence data was identified in the evidence collected.
BS3	Not assessed	No calibrated functional assay data demonstrating proficient MMR function (functional odds for pathogenicity ≤0.05 or >0.05 & ≤0.48) is available for this specific variant. The VCEP functional assay SVI documentation does not list this variant.	vcep_functional_assay_svi_documentation_mmr
BS4	Not assessed	BS4 under the MSH6 VCEP requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting VCEP thresholds. No segregation data is available for this variant.
BP1	N/A	BP1 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0 (missense variant in gene where only LOF causes disease is not applicable).	cspec
BP2	N/A	BP2 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0.	cspec
BP3	N/A	BP3 is explicitly listed as Not Applicable by the MSH6 VCEP v2.0.0 (in-frame deletions/insertions in repetitive region without known function is not used).	cspec
BP4	N/A	BP4 under the MSH6 VCEP applies to missense variants with HCI prior probability <0.11 or intronic/synonymous variants with SpliceAI delta score ≤0.1. This is a nonsense variant and does not fall under BP4 applicability.
BP5	Not met	BP5 requires tumors showing MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in MSI-H tumors. The evidence from PMID 37318702 shows the opposite: both tumors (EC and CRC) were MSH6-deficient with loss of MSH6 protein expression, consistent with pathogenicity. BP5 is not met.
BP6	N/A	BP6 is explicitly listed as Not Applicable for this VCEP by the MSH6 VCEP v2.0.0, per ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 under the MSH6 VCEP applies to synonymous (silent) or intronic variants at or beyond -21/+7. This is a frameshift/nonsense variant and does not fall under BP7 applicability.

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