Variant classification summary

NM_000179.3:c.4T>A

MSH6 · NP_000170.1:p.(Ser2Thr) · NM_000179.3

GRCh37: chr2:48010376 T>A · GRCh38: chr2:47783237 T>A

Gene: MSH6 Transcript: NM_000179.3

Final call

PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ser2Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 c.4T>A (p.Ser2Thr) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v4.1 and gnomAD v2.1, which meets the MSH6 VCEP PM2 threshold for supporting evidence because the observed allele frequency is below 0.00002.

3

For this MSH6 missense variant, the HCI prior probability is 0.0038, below the BP4 threshold of 0.11 and consistent with benign computational evidence; REVEL is 0.405 and BayesDel is -0.114406.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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	Not met	This variant is a missense change, NM_000179.3:c.4T>A (p.Ser2Thr), and does not alter the MSH6 initiation codon. The MSH6 VCEP PVS1 rules are intended for truncating variants, qualifying splice defects, exon-level genomic losses, or initiation codon variants, so this variant does not meet PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified that a different nucleotide change causing the same p.Ser2Thr amino acid substitution has been previously established as pathogenic or likely pathogenic by this VCEP.	cspec
PS2	Not assessed	No confirmed de novo occurrence with appropriate parental confirmation was identified for this variant.	cspec clinvar
PS3	Not assessed	No calibrated functional study showing a damaging effect for this specific variant was identified.	cspec oncokb
PS4	N/A	PS4 is not used in this MSH6 VCEP framework.	cspec
PM1	N/A	PM1 is not used in this MSH6 VCEP framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. Under the MSH6 VCEP rule, absence or an allele frequency below 0.00002 in gnomAD v4 supports PM2 at supporting strength, so this criterion is met.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No confirmed in trans observations with a pathogenic MSH6 variant in an appropriate constitutional mismatch repair deficiency context were identified.	cspec
PM4	N/A	PM4 is not used in this MSH6 VCEP framework.	cspec
PM5	Not assessed	No evidence was identified that a different missense change at codon 2 has been established by this VCEP as pathogenic or likely pathogenic on the protein level.	cspec
PM6	N/A	PM6 is not used in this MSH6 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so a Bayes likelihood ratio for co-segregation could not be calculated.	cspec clinvar
PP2	N/A	PP2 is not used in this MSH6 VCEP framework.	cspec
PP3	Not met	For MSH6 missense variants, the VCEP uses the HCI prior probability. This variant has an HCI prior probability of 0.0038, which is well below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI shows a max delta score of 0.27, but the MSH6 splice PP3 rule is intended for non-canonical splicing nucleotides, and this exonic missense variant does not meet that rule.	hci_prior spliceai revel bayesdel cspec
PP4	Not assessed	No tumor microsatellite instability results or mismatch repair immunohistochemistry findings were identified to support an MSH6-consistent Lynch syndrome tumor phenotype.	cspec
PP5	N/A	PP5 is not used in this MSH6 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so it is below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%). BA1 is not met.	gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v4.1, so it is below the MSH6 VCEP BS1 range of 0.00022 to <0.0022. BS1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in trans with a known pathogenic MSH6 variant in an individual whose clinical findings argue against constitutional mismatch repair deficiency.	cspec
BS3	Not assessed	No calibrated functional study showing retained MSH6 function for this variant was identified.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.	cspec clinvar
BP1	N/A	BP1 is not used in this MSH6 VCEP framework.	cspec
BP2	N/A	BP2 is not used in this MSH6 VCEP framework.	cspec
BP3	N/A	BP3 is not used in this MSH6 VCEP framework.	cspec
BP4	Met	For MSH6 missense variants, the VCEP uses the HCI prior probability for BP4. This variant has an HCI prior probability of 0.0038, which is below the BP4 threshold of 0.11, supporting a benign computational interpretation. REVEL is 0.405 and BayesDel is -0.114406, and these do not override the MSH6-specific HCI prior rule.	hci_prior revel bayesdel cspec
BP5	Not assessed	No tumor findings were identified that would argue against this variant being the cause of an MSH6-related disorder.	cspec
BP6	N/A	BP6 is not used in this MSH6 VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants. This variant is missense, so BP7 is not applicable.	cspec

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