Variant classification summary

NM_000179.3:c.-2G>T

MSH6 · NP_000170.1:p.? · NM_000179.3

GRCh37: chr2:48010371 G>T · GRCh38: chr2:47783232 G>T

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.?

gnomAD AF

1.2413293147365651e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 NM_000179.3:c.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.

2

This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 1.24133e-05 (20/1611176 alleles) and gnomAD v2.1 total allele frequency 1.45244e-05 (4/275398 alleles), which supports PM2_Supporting under the MSH6 VCEP threshold of less than 0.00002.

3

Available evidence does not show a qualifying constitutional RNA or other calibrated functional study for this variant, so PS3 and BS3 are not currently supported.

4

SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.00, but this 5′ UTR substitution does not fit the MSH6 VCEP PP3 or BP4 rule types for missense or qualifying intronic/non-canonical splice variants.

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 is 2.987e-05, which is below the MSH6 VCEP BA1 threshold of 0.0022, so BA1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No confirmed in trans observation with a pathogenic MSH6 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 was not assessed.	cspec vcep_table_for_cmmrd_diagnosis
BP6	N/A	BP6 is not used by this MSH6 VCEP specification.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified for this variant, so PP4 was not assessed.	cspec
PP1	Not assessed	No segregation data were identified to calculate the Bayes likelihood ratio required for PP1, so this criterion was not assessed.	cspec PMID:25070057
BS1	Not met	The gnomAD v4.1 filtering allele frequency is 2.987e-05, which is below the MSH6 VCEP BS1 threshold of 0.00022, so BS1 is not met.	gnomad_v4 cspec
BP7	N/A	This is a 5′ UTR substitution at c.-2 rather than a synonymous change or an intronic variant at or beyond the BP7 distance rule, so BP7 is not applicable.	cspec
PP2	N/A	PP2 is not used by this MSH6 VCEP specification.	cspec
BP3	N/A	BP3 is not used by this MSH6 VCEP specification.	cspec
BP1	N/A	BP1 is not used by this MSH6 VCEP specification.	cspec
BS3	Not assessed	No variant-specific RNA or other calibrated functional assay showing no damaging effect was identified, so BS3 was not assessed.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr PMID:26888055
PM2	Met	This variant is present at very low frequency in gnomAD v4.1 with a total allele frequency of 1.24133e-05 (20/1611176 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002, so PM2_Supporting is met.	gnomad_v4 gnomad_v2 cspec
BP4	N/A	SpliceAI predicts no significant splice impact with a max delta score of 0.00, but the MSH6 VCEP BP4 rule is specified for missense variants using HCI priors or for intronic and synonymous variants, and this c.-2 5′ UTR substitution does not fit those rule types, so BP4 is not applied.	spliceai cspec
PS1	N/A	This variant is neither a missense substitution nor a non-canonical splice nucleotide with a previously established pathogenic comparator, so PS1 is not applicable.	cspec
PS2	Not assessed	No de novo data were identified, so PS2 was not assessed.	cspec
BP5	Not assessed	No qualifying evidence for an alternate molecular explanation with mismatch repair findings inconsistent with MSH6 was identified, so BP5 was not assessed.	cspec
PVS1	Not met	Although the generic scaffold flagged canonical splice review, this variant is annotated as NM_000179.3:c.-2G>T, a 5′ UTR substitution immediately upstream of the coding start. It does not alter the initiation codon and does not meet the MSH6 VCEP null-variant categories for nonsense, frameshift, canonical ±1/2 splice, or qualifying RNA-proven splice defects, so PVS1 is not applied.	cspec pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PP5	N/A	PP5 is not used by this MSH6 VCEP specification.	cspec
BP2	N/A	BP2 is not used by this MSH6 VCEP specification.	cspec
PS4	N/A	PS4 is not used by this MSH6 VCEP specification.	cspec
PM4	N/A	PM4 is not used by this MSH6 VCEP specification.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay or constitutional RNA study demonstrating an abnormal effect was identified, so PS3 was not assessed.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr PMID:26888055
PP3	N/A	The MSH6 VCEP PP3 rule is specified for missense variants using HCI priors or for predicted splice defects at non-canonical splice nucleotides with SpliceAI delta score at least 0.2. This c.-2 5′ UTR substitution is not missense, is not a non-canonical splice nucleotide, and SpliceAI shows a max delta score of 0.00, so PP3 is not applied.	spliceai cspec
PM6	N/A	PM6 is not used by this MSH6 VCEP specification.	cspec
PM1	N/A	PM1 is not used by this MSH6 VCEP specification.	cspec
PM3	Not assessed	No qualifying in trans observations for constitutional mismatch repair deficiency scoring were identified, so PM3 was not assessed.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No segregation data showing lack of co-segregation with disease were identified, so BS4 was not assessed.	cspec PMID:25070057
PM5	N/A	The MSH6 PM5 rule uses classic same-residue missense logic, and this variant is not missense-like, so PM5 is not applicable.	pm5_candidates cspec

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