Variant classification summary

NM_000179.3:c.942C>G

MSH6 · NP_000170.1:p.(Ser314Arg) · NM_000179.3

GRCh37: chr2:48026064 C>G · GRCh38: chr2:47798925 C>G

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BS1 strong

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ser314Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 c.942C>G (p.Ser314Arg) variant has been reported in ClinVar, where most submissions are classified as likely benign or benign, with additional submissions classified as uncertain significance.

2

In gnomAD v4.1, this variant is present at an overall allele frequency of 0.0000223049 (36/1613998 alleles), and the grpmax filtering allele frequency is 0.00027673, which is above the MSH6 BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.

3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00; however, no HCI prior probability result was identified to support missense PP3 or BP4 assessment under the MSH6 specification.

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
BA1	Not met	This variant is present in gnomAD v4.1, but the grpmax filtering allele frequency is 0.00027673 (0.027673%), which is below the MSH6 BA1 threshold of 0.0022 (0.22%); therefore BA1 is not met.	gnomad_v4 cspec
BS1	Met	This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.00027673 (0.027673%), which is above the MSH6 BS1 threshold of 0.00022 (0.022%) and below the BA1 threshold of 0.0022 (0.22%); this supports BS1 at Strong strength.	gnomad_v4 cspec
BS2	Not assessed	No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual without evidence of constitutional mismatch repair deficiency was identified, so BS2 cannot be applied.	cspec vcep_table_for_cmmrd_diagnosis
BS3	Not assessed	No variant-specific calibrated functional assay or qualifying proficient-function result was identified for this variant, so BS3 cannot be applied.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	No segregation dataset showing lack of co-segregation with disease was identified, so BS4 cannot be applied.	cspec
BP1	N/A	BP1 is not applicable for MSH6 under this gene-specific framework.	cspec
BP2	N/A	BP2 is not applicable for MSH6 under this gene-specific framework.	cspec
BP3	N/A	BP3 is not applicable for MSH6 under this gene-specific framework.	cspec
BP4	Not assessed	This is a missense variant. The MSH6 missense BP4 rule requires an HCI prior probability of pathogenicity below 0.11, and no HCI prior result was identified. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but the intronic/synonymous SpliceAI branch of BP4 does not apply to this missense change.	cspec spliceai
BP5	Not assessed	No tumor profile showing mismatch between the observed tumor findings and MSH6-related disease was identified, so BP5 cannot be applied.	cspec
BP6	N/A	BP6 is not applicable for MSH6 under this gene-specific framework.	cspec
BP7	N/A	This variant is a missense substitution, not a synonymous or qualifying deep intronic change, so BP7 does not apply.	cspec
PP1	Not assessed	No family segregation data with a calculable Bayes likelihood ratio were identified, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not applicable for MSH6 under this gene-specific framework.	cspec
PP3	Not assessed	This is a missense variant. The MSH6 missense PP3 rule requires an HCI prior probability above 0.68 for Supporting or above 0.81 for Moderate, and no HCI prior result was identified. SpliceAI predicts no significant splice impact with a max delta score of 0.00, so the non-canonical splicing branch of PP3 is also not met.	cspec spliceai
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry findings were identified for this case, so PP4 cannot be applied.	cspec
PP5	N/A	PP5 is not applicable for MSH6 under this gene-specific framework.	cspec
PVS1	Not met	This variant is a missense substitution, p.(Ser314Arg), and does not fall into the MSH6 PVS1 null-variant categories. The generic PVS1 assessment also indicates that this variant is not a nonsense, frameshift, or canonical ±1/2 splice variant, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No VCEP-established pathogenic or likely pathogenic alternate nucleotide change producing the same amino acid substitution was identified, so PS1 cannot be applied.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not assessed	No confirmed de novo occurrence data were identified, so PS2 cannot be applied.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay or qualifying mismatch repair defect result was identified for this variant, so PS3 cannot be applied.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	PS4 is not applicable for MSH6 under this gene-specific framework.	cspec
PM1	N/A	PM1 is not applicable for MSH6 under this gene-specific framework.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at an overall allele frequency of 0.0000223049 (36/1613998 alleles), which is above the MSH6 PM2 threshold of less than 0.00002 (<1 in 50,000 alleles); therefore PM2 is not met.	gnomad_v4 cspec
PM3	Not assessed	No data supporting occurrence with another pathogenic MSH6 variant in the constitutional mismatch repair deficiency framework were identified, so PM3 cannot be applied.	cspec
PM4	N/A	PM4 is not applicable for MSH6 under this gene-specific framework.	cspec
PM5	Not assessed	No VCEP-established pathogenic or likely pathogenic missense variant at codon 314 was identified for this review, and PP3 is not met for this variant; therefore PM5 cannot be applied.	cspec vcep_vcep_pilot_variants_mmr
PM6	N/A	PM6 is not applicable for MSH6 under this gene-specific framework.	cspec

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