Variant classification summary

NM_000179.3:c.3334G>A

MSH6 · NP_000170.1:p.(Asp1112Asn) · NM_000179.3

GRCh37: chr2:48030720 G>A · GRCh38: chr2:47803581 G>A

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Asp1112Asn)

gnomAD AF

4.7088096872606874e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 NM_000179.3:c.3334G>A (p.Asp1112Asn, p.D1112N) variant has been reported in ClinVar with predominantly uncertain significance submissions and a smaller number of likely benign submissions.

2

This variant is present in population databases, including gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709; grpmax FAF 0.00004535) and gnomAD v2.1 at 8/282750 alleles (AF 0.00002829), and is absent from gnomAD-Canada; the gnomAD v4.1 frequency is above the MSH6 PM2 threshold of <0.00002 but below the BS1 threshold of 0.00022.

3

For MSH6 missense prediction, the HCI prior probability is 0.5901, which is below the PP3 thresholds of >0.68 and >0.81 and above the BP4 threshold of <0.11; REVEL is 0.71, BayesDel is -0.0786, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04.

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	The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BA1 threshold of 0.0022, so BA1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusions was identified, so BS2 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BP6	N/A	BP6 is not used by this VCEP.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry results were identified to support the MSH6-specific PP4 tumor phenotype thresholds.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.	cspec
BS1	Not met	The gnomAD v4.1 filtering allele frequency for this variant is 0.00004535, which is below the MSH6 BS1 threshold of 0.00022, so BS1 is not met.	gnomad_v4 cspec
BP7	N/A	This is a missense variant, not a synonymous or qualifying deep intronic variant, so BP7 is not applicable.	cspec
PP2	N/A	PP2 is not used by this VCEP.	cspec
BP3	N/A	BP3 is not used by this VCEP.	cspec
BP1	N/A	BP1 is not used by this VCEP.	cspec
BS3	Not assessed	No variant-specific calibrated functional evidence showing proficient MMR function or normal RNA effect was identified, so BS3 cannot be applied.	cspec oncokb
PM2	Not met	This variant is present in gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709), which is above the MSH6 PM2 threshold of <0.00002, so PM2 is not met. It is absent from gnomAD-Canada, but the gnomAD v4.1 frequency exceeds the VCEP rarity cutoff.	gnomad_v4 gnomad_canada cspec
BP4	Not met	For MSH6 missense variants, BP4 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is above the BP4 threshold of <0.11, so BP4 is not met. SpliceAI shows a low maximum delta score of 0.04, but the missense-specific HCI prior rule does not support BP4 here.	hci_prior spliceai cspec
PS1	Not assessed	No previously established pathogenic or likely pathogenic alternate nucleotide change producing the same amino acid substitution was identified, so PS1 cannot be applied from the available evidence.	cspec
PS2	Not assessed	No confirmed de novo data were identified, so PS2 cannot be assessed.	cspec
BP5	Not assessed	No tumor findings showing MSS, retained MMR protein expression, or inconsistent MMR loss patterns were identified, so BP5 cannot be assessed.	cspec
PVS1	N/A	This is a missense variant, not a truncating or canonical splice variant, and the variant-specific PVS1 assessment states that it does not fall into a default null-variant bucket. PVS1 is therefore not applicable.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not used by this VCEP.	cspec
BP2	N/A	BP2 is not used by this VCEP.	cspec
PS4	N/A	PS4 is not used by this VCEP.	cspec
PM4	N/A	PM4 is not used by this VCEP.	cspec
PS3	Not assessed	No variant-specific calibrated functional evidence showing an MMR defect or marked allelic expression loss was identified, so PS3 cannot be applied.	cspec oncokb
PP3	Not met	For MSH6 missense variants, PP3 uses the HCI prior. The HCI prior probability for this variant is 0.5901, which is below the PP3_Supporting threshold of >0.68 and below the PP3_Moderate threshold of >0.81, so PP3 is not met. REVEL is 0.71 and BayesDel is -0.0786, but the VCEP missense rule prioritizes the HCI prior for MSH6. SpliceAI predicts no significant splice effect with a maximum delta score of 0.04.	hci_prior revel bayesdel spliceai cspec
PM6	N/A	PM6 is not used by this VCEP.	cspec
PM1	N/A	PM1 is not used by this VCEP.	cspec
PM3	Not assessed	No qualifying observations in trans with another pathogenic MSH6 variant in the constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No non-segregation data were identified, so BS4 cannot be applied.	cspec
PM5	Not assessed	No verified same-residue pathogenic or likely pathogenic missense comparator at codon 1112 was identified from the available comparator materials, so PM5 cannot be applied from the current evidence. In addition, the MSH6 VCEP requires missense PM5 to be used only when PP3 is met for the index variant, which is not the case here.	cspec pm5_candidates

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