Variant classification summary

NM_000179.3:c.3483T>C

MSH6 · NP_000170.1:p.(Pro1161=) · NM_000179.3

GRCh37: chr2:48032093 T>C · GRCh38: chr2:47804954 T>C

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BP7 supporting PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Pro1161=)

gnomAD AF

1.858671570255307e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 4 likely benign and 1 benign clinical laboratory submissions.

2

This variant is rare in population databases, with gnomAD v4.1 overall AF 1.86e-06 (3/1,614,056 alleles) and highest observed subpopulation AF 3.20e-05 (2/62,482 alleles), which is below the MSH6 BS1 threshold of 0.00022 and BA1 threshold of 0.0022 but within the PM2_Supporting rarity threshold of <0.00002.

3

This is a synonymous change, NP_000170.1:p.(Pro1161=), located 44 nucleotides from the exon 6 acceptor and 73 nucleotides from the donor, and SpliceAI predicts no splice effect (max delta score 0.00), supporting BP7 and BP4 rather than PP3.

Final determination: Rule19 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 Likely Benign.

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 data do not meet BA1. In gnomAD v4.1, the highest observed subpopulation allele frequency is 0.00320% (2/62,482 alleles), which is below the MSH6 BA1 threshold of 0.22%.	gnomad_v4 cspec
BS2	Not assessed	No phase-confirmed in trans observation with a known pathogenic MSH6 variant in an older patient without clinical features of CMMRD was identified, so BS2 cannot be assessed from the available evidence.	cspec
BP6	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified, so PP4 cannot be assessed.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 cannot be assessed.	cspec
BS1	Not met	Population data do not meet BS1. In gnomAD v4.1, the highest observed subpopulation allele frequency is 0.00320% (2/62,482 alleles), which is below the MSH6 BS1 range of 0.022% to 0.22%.	gnomad_v4 cspec
BP7	Met	This is a synonymous MSH6 variant, NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)), located well away from the splice junctions in exon 6 (44 nucleotides from the acceptor and 73 nucleotides from the donor), which satisfies the BP7 location requirement for a silent exonic change beyond -21/+7.	cspec
PP2	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP3	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP1	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BS3	Not assessed	No RNA study with nonsense-mediated decay inhibition or other qualifying calibrated benign functional assay was identified for this variant, so BS3 cannot be assessed.	cspec
PM2	Met	This variant is extremely rare in population databases. In gnomAD v4.1, the overall allele frequency is 1.86e-06 (3/1,614,056 alleles), which is below the MSH6 PM2_Supporting threshold of 0.00002.	gnomad_v4 cspec
BP4	Met	Computational splice prediction supports a benign interpretation. For this synonymous variant, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 BP4 threshold of 0.1 for no predicted splicing impact.	spliceai cspec
PS1	N/A	The MSH6 PS1 rule applies to missense substitutions causing the same amino acid change or to variants affecting the same non-canonical splice nucleotide as a known pathogenic or likely pathogenic splice variant. This synonymous exonic change does not fit those PS1 use cases.	cspec
PS2	Not assessed	No confirmed de novo data were identified, so PS2 cannot be assessed.	cspec
BP5	Not assessed	No tumor data showing mismatch repair findings inconsistent with MSH6-related disease were identified, so BP5 cannot be assessed.	cspec
PVS1	Not met	PVS1 is not met. This variant is a synonymous change, NP_000170.1:p.(Pro1161=), and does not fall into the MSH6 null-variant categories used for PVS1. No RNA evidence was identified showing a splice aberration that would create a loss-of-function effect.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP2	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PS4	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PM4	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PS3	Not assessed	No calibrated pathogenic functional assay or variant-specific RNA evidence demonstrating an abnormal effect was identified, so PS3 cannot be assessed.	cspec
PP3	Not met	Computational evidence does not support PP3. For non-canonical splice prediction, SpliceAI shows a maximum delta score of 0.00, which is below the MSH6 PP3 threshold of 0.2. The HCI prior rule applies to missense variants and is not relevant to this synonymous change.	spliceai cspec
PM6	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PM1	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PM3	Not assessed	No qualifying recessive phase data or point-based in trans observations were identified, so PM3 cannot be assessed.	cspec
BS4	Not assessed	No non-segregation data were identified, so BS4 cannot be assessed.	cspec
PM5	N/A	PM5 is not applicable because the MSH6 PM5 rule is restricted to classic same-residue missense comparisons, and this variant is synonymous rather than missense.	cspec pm5_candidates

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.