Variant classification summary

NM_000179.2:c.3412G>A

MSH6 · NP_000170.1:p.(Gly1138Arg) · NM_000179.2

GRCh37: chr2:48030798 G>A · GRCh38: chr2:47803659 G>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.(Gly1138Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,614,568 alleles) and gnomAD v2.1, meeting the VCEP threshold of allele frequency <0.00002.

2

PP3_Moderate is met: the HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, exceeding the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.

3

PVS1 is not applicable: this is a missense variant (p.Gly1138Arg), not a null variant, and SpliceAI predicts no splice impact (max delta = 0.01).

4

PS3 is not met: no calibrated functional assay data exists for p.Gly1138Arg in the VCEP functional assay documentation or published literature.

5

PS1, PS2, PM5, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4, BP5 are not met due to absence of supporting evidence.

6

PS4, PS5, PM1, PM6, PP2, PP5, BP1, BP2, BP3, BP6, BP7, PM3, PM4 are not applicable per the InSiGHT MMR VCEP v2.0.0 specifications or because the variant class does not meet the criterion definition.

Final determination: No criteria-combination rule matched the adjudicated criteria 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 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	This is a missense variant (p.Gly1138Arg). PVS1 per the MSH6 VCEP v2.0.0 applies only to null variants (nonsense/frameshift introducing PTC ≤ codon 1341, canonical splice variants, or confirmed splicing aberrations). SpliceAI predicts no splice impact (max delta = 0.01).	spliceai cspec
PS1	Not met	No different nucleotide change encoding the same amino acid (p.Gly1138Arg) has been established as Pathogenic by the InSiGHT MMR VCEP. No alternate nucleotide substitution at codon 1138 was identified in ClinVar or the VCEP pilot variant spreadsheet.	cspec clinvar vcep_vcep_pilot_variants_mmr
PS2	Not met	No de novo occurrence has been reported for this variant. De novo events in Lynch syndrome genes are rare; no evidence was identified in ClinVar, literature, or exploratory search.	clinvar
PS3	Not met	No calibrated functional assay data exists for p.Gly1138Arg. The VCEP functional assay SVI documentation spreadsheet (Drost 2018/2020, Jia/Scott 2021/2022, Rath 2022, Thompson 2013, Morak 2019, Bouvet 2019 datasets) does not include this variant. No variant-specific functional evidence was identified in the literature.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
PS5	N/A	PS5 is not defined in the InSiGHT MMR VCEP v2.0.0 framework for MSH6.	cspec
PM1	N/A	PM1 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
PM2	Met	The variant is absent from gnomAD v4.1 (0 alleles across 1,614,568 total alleles) and gnomAD v2.1. This meets the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).	gnomad_v4 gnomad_v2 cspec
PM5	Not met	No alternate missense change at codon 1138 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP. PM5 additionally requires PP3 to be met for the variant under assessment; PP3 is met at moderate strength, but the prerequisite comparator is absent.	cspec clinvar vcep_vcep_pilot_variants_mmr
PM6	N/A	PM6 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
PP1	Not met	No co-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant. No family studies with segregation analysis were identified.	clinvar
PP2	N/A	PP2 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
PP3	Met	The HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, which exceeds the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.	hci_prior revel cspec
PP4	Not met	No MSI-H tumor data or MMR protein expression data (IHC) specific to this variant has been reported. PP4 requires CRC/endometrial MSI-H tumors and/or loss of MMR protein expression consistent with MSH6.	cspec
PP5	N/A	PP5 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The variant is absent from gnomAD v4.1 (0 alleles). The VCEP BA1_StandAlone threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%). An absent variant does not meet this threshold.	gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4.1. The VCEP BS1_Strong threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022. An absent variant does not meet this threshold.	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 has been reported. Confirmation of phase requires testing of parents or offspring, which has not been performed.	cspec
BS3	Not met	No calibrated functional assay data showing a benign effect (functional odds for pathogenicity ≤ 0.05 for Strong or ≤ 0.48 for Supporting) exists for p.Gly1138Arg. The VCEP functional assay dataset does not include this variant.	vcep_functional_assay_svi_documentation_mmr cspec
BS4	Not met	No lack-of-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant. No family studies demonstrating absence of co-segregation with disease were identified.	cspec
BP1	N/A	BP1 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
BP2	N/A	BP2 is designated Not Applicable under the InSiGHT MMR VCEP v2.0.0 specifications for MSH6.	cspec
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a single-nucleotide missense substitution.
BP4	Not met	The HCI prior probability of pathogenicity for c.3412G>A is 0.9617, which is far above the VCEP BP4_Supporting threshold of <0.11. The missense-specific BP4 rule does not apply. SpliceAI predicts no splicing impact (max delta = 0.01), but the BP4 rule for synonymous/intronic variants is not applicable to this missense variant.	hci_prior spliceai cspec
BP5	Not met	No tumor data demonstrating MSS status or BRAF V600E/MLH1 methylation has been reported for patients carrying this variant. BP5 requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or alternative molecular etiology.	cspec
BP6	N/A	BP6 is designated Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. This is a missense variant (c.3412G>A, p.Gly1138Arg) and does not qualify.	cspec
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. Lynch syndrome is autosomal dominant and PM3 is not applicable in this context.
PM4	N/A	PM4 applies to non-repeat region in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution.

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