Variant classification summary

NM_000179.3:c.836G>A

MSH6 · NP_000170.1:p.(Ser279Asn) · NM_000179.3

GRCh37: chr2:48025958 G>A · GRCh38: chr2:47798819 G>A

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ser279Asn)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.3:c.836G>A (p.Ser279Asn) is a missense variant in MSH6 exon 4 that is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (allele frequency <0.00002).

2

Computational in silico predictors, including the MSH6-specific HCI prior probability of 0.0075, are consistent with a benign impact, meeting the VCEP BP4_Supporting criterion (HCI prior <0.11). SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.322 and BayesDel is -0.109.

3

No functional assay data, segregation data, de novo observations, tumor phenotype data, or same-residue pathogenic comparator variants are available for this variant. The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories; ClinVar ID 234915) and has been observed once in somatic cancers (COSMIC COSV113286823).

4

Per the MSH6 VCEP v2.0.0 combination rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) are equivocal, resulting in a final classification of Uncertain Significance (VUS).

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
PVS1	N/A	Missense variant p.(Ser279Asn); does not meet any MSH6 VCEP v2.0.0 PVS1 null-variant criteria (not nonsense, frameshift, canonical splice, initiation codon, or exon-level deletion).	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No alternate nucleotide change at codon 279 encoding p.Ser279Asn has been classified as Pathogenic by the MSH6 VCEP.	cspec clinvar
PS2	Not met	No de novo occurrences with confirmed parentage have been reported for NM_000179.3:c.836G>A.
PS3	Not met	No calibrated functional assay data with functional odds for pathogenicity are available for this variant. The VCEP functional assay documentation does not include c.836G>A.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
PS5	N/A	PS5 is not included in the MSH6 VCEP v2.0.0 specification and is not used in this framework.	cspec
PM1	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
PM2	Met	Absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting allele frequency threshold of <0.00002 (<1 in 50,000 alleles).	gnomad_v4 gnomad_v2 cspec
PM5	Not met	No missense variant at codon 279 has been classified as Pathogenic or Likely Pathogenic on the protein level by the MSH6 VCEP; PM5 requires an established P/LP comparator at the same residue.	pm5_candidates cspec clinvar
PM6	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
PP1	Not met	No cosegregation data with computed Bayes Likelihood Ratio are available for this variant.
PP2	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
PP3	Not met	HCI prior probability 0.0075 does not meet VCEP missense thresholds (>0.68 for PP3_Supporting, >0.81 for PP3_Moderate). SpliceAI max delta score 0.00 does not meet the non-canonical splice threshold (>=0.2).	hci_prior spliceai cspec
PP4	Not met	No MSI-H tumor data or MMR protein expression loss data consistent with the variant location have been reported for c.836G>A.	cspec
PP5	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
BA1	Not met	Absent from gnomAD v4.1; does not meet the VCEP BA1 Stand-Alone threshold of Grpmax filtering AF >= 0.0022 (0.22%).	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Absent from gnomAD v4.1; does not meet the VCEP BS1 Strong threshold of Grpmax filtering AF >= 0.00022 (0.022%).	gnomad_v4 gnomad_v2 cspec
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features.	cspec
BS3	Not met	No calibrated functional assay data showing functional odds for pathogenicity <= 0.48 for this variant. The VCEP functional assay documentation does not include c.836G>A.	vcep_functional_assay_svi_documentation_mmr cspec
BS4	Not met	No lack-of-segregation data with computed Bayes Likelihood Ratio are available for this variant.	cspec
BP1	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
BP2	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification.	cspec
BP4	Met	HCI prior probability for pathogenicity is 0.0075, which is below the MSH6 VCEP BP4_Supporting threshold of <0.11 for missense variants. Multiple lines of computational evidence suggest no deleterious impact.	hci_prior spliceai revel bayesdel cspec
BP5	Not met	No MSS tumor data or MMR protein expression data demonstrating inconsistent MMR protein loss have been reported for this variant.	cspec
BP6	N/A	This criterion is Not Applicable per the MSH6 VCEP v2.0.0 specification as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	Missense variant c.836G>A (p.Ser279Asn); BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions per VCEP specification.	cspec spliceai

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