NM_000179.3:c.199C>A

MSH6 · NP_000170.1:p.(Pro67Thr) · NM_000179.3

GRCh37: chr2:48010571 C>A · GRCh38: chr2:47783432 C>A

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Pro67Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH6 c.199C>A (p.Pro67Thr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with mostly uncertain significance submissions and one benign submission.

This variant is extremely rare in gnomAD v4.1, where it is present in 1 of 1,501,316 alleles (AF 6.66082e-07) with a highest observed population frequency of 8.86721e-07 in non-Finnish Europeans, which is below the MSH6 PM2_Supporting threshold of 0.00002.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational scores are low or benign-leaning (REVEL 0.161; BayesDel -0.32103), although the MSH6 VCEP missense PP3/BP4 rule requires an HCI prior probability that was not available here.

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	Population frequency does not meet the MSH6 BA1 threshold. In gnomAD v4.1, this variant is present in 1/1,501,316 alleles (AF 6.66082e-07), with the highest observed population frequency 8.86721e-07 in non-Finnish Europeans; both values are below the BA1 threshold of 0.0022.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified that this variant occurred in trans with a known pathogenic MSH6 variant in an individual meeting the VCEP clinical conditions for BS2. Available data do not support or refute this criterion.	cspec vcep_table_for_cmmrd_diagnosis
BP6	N/A	This criterion is not applicable because the MSH6 VCEP does not use BP6.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry data were identified for this variant. Available evidence does not support application of the MSH6 VCEP PP4 tumor-based rule.	cspec
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not show co-segregation with Lynch syndrome-associated disease in informative families.	cspec
BS1	Not met	Population frequency does not meet the MSH6 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 8.86721e-07 in non-Finnish Europeans, which is below the BS1 range of 0.00022 to less than 0.0022.	gnomad_v4 cspec
BP7	Not met	This is a missense variant, p.(Pro67Thr), rather than a synonymous or qualifying intronic variant. BP7 does not apply to this variant type.	cspec
PP2	N/A	This criterion is not applicable because the MSH6 VCEP does not use PP2.	cspec
BP3	N/A	This criterion is not applicable because the MSH6 VCEP does not use BP3.	cspec
BP1	N/A	This criterion is not applicable because the MSH6 VCEP does not use BP1.	cspec
BS3	Not assessed	No variant-specific functional study was identified showing retained mismatch repair function or a benign RNA result that would satisfy the MSH6 VCEP BS3 rule. Available evidence is insufficient to apply BS3.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PM2	Met	This variant is extremely rare in population databases. In gnomAD v4.1, it is present in 1/1,501,316 alleles (AF 6.66082e-07), which is below the MSH6 PM2_Supporting threshold of 0.00002.	gnomad_v4 cspec
BP4	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational scores are low or benign-leaning (REVEL 0.161; BayesDel -0.32103). However, for MSH6 missense variants the VCEP BP4 rule is based on HCI prior probability less than 0.11, and no HCI prior score was identified here, so BP4 cannot be assigned from the available evidence.	cspec spliceai revel bayesdel
PS1	Not assessed	No evidence was identified that the same amino acid change, p.(Pro67Thr), has previously been established by this VCEP as pathogenic or likely pathogenic due to a different nucleotide change. Available evidence is insufficient to apply PS1.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not assessed	No de novo observation was identified for this variant. Available evidence does not support application of PS2.	cspec
BP5	Not assessed	No tumor findings were identified showing microsatellite stable disease, intact mismatch repair expression, or mismatch between tumor pattern and the gene involved. Available evidence does not support application of BP5.	cspec
PVS1	Not met	This variant is a missense substitution, p.(Pro67Thr), and does not create a premature termination codon or canonical splice-site change. The gene-level context supports loss of function as an established disease mechanism in MSH6, but the variant-level assessment does not place this change in a PVS1 null-variant category, so PVS1 is not applied.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	This criterion is not applicable because the MSH6 VCEP does not use PP5.	cspec
BP2	N/A	This criterion is not applicable because the MSH6 VCEP does not use BP2.	cspec
PS4	N/A	This criterion is not applicable because the MSH6 VCEP does not use PS4.	cspec
PM4	N/A	This criterion is not applicable because the MSH6 VCEP does not use PM4.	cspec
PS3	Not assessed	No variant-specific functional study was identified showing mismatch repair deficiency or pathogenic functional odds that would satisfy the MSH6 VCEP PS3 rule. Available evidence is insufficient to apply PS3.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PP3	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), REVEL is 0.161, and BayesDel is -0.32103, which do not support a damaging computational profile. However, for MSH6 missense variants the VCEP PP3 rule is based on HCI prior probability greater than 0.68, and no HCI prior score was identified here, so PP3 cannot be assigned from the available evidence.	cspec spliceai revel bayesdel
PM6	N/A	This criterion is not applicable because the MSH6 VCEP does not use PM6.	cspec
PM1	N/A	This criterion is not applicable because the MSH6 VCEP does not use PM1.	cspec
PM3	Not assessed	No evidence was identified that this variant occurred with another pathogenic MSH6 variant in a configuration and clinical setting that would generate PM3 points. Available evidence is insufficient to apply PM3.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No non-segregation data were identified for this variant. Available evidence does not show lack of co-segregation with disease in informative families.	cspec
PM5	Not assessed	No evidence was identified that a different missense change at codon 67 has been established by this VCEP as pathogenic or likely pathogenic on the protein level and independent of splicing. Available evidence is insufficient to apply PM5.	cspec vcep_vcep_pilot_variants_mmr

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