NM_002439.5:c.2006G>A

MSH3 · NP_002430.3:p.(Arg669Gln) · NM_002439.5

GRCh37: chr5:80063861 G>A · GRCh38: chr5:80768042 G>A

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Arg669Gln)

gnomAD AF

4.462492748449284e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: gnomAD v4.1 shows an allele frequency of 4.46249e-05 with zero homozygotes.

BP4 supporting: REVEL score 0.202 is below the generic BP4 threshold of 0.29.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion (PM2) plus one supporting benign criterion (BP4) does not meet any defined pathogenic, likely pathogenic, benign, or likely benign combination, resulting in VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002439.5:c.2006G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Arg669Gln). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated alternate-codon variant producing the same p.Arg669Gln amino-acid change was identified.
PS2	Not assessed	Not assessed: no confirmed proband de novo observation or parental testing showing absence of NM_002439.5:c.2006G>A in both biological parents.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay or controlled biological readout demonstrating that MSH3 p.Arg669Gln impairs function was identified.	clinvar PMID:25741868
PS4	Not assessed	Not assessed: no case-control counts, enrichment statistic, or variant-specific affected-patient cohort is available for c.2006G>A.	clinvar PMID:24905773 PMID:24929052 PMID:25394175 PMID:25741868 PMID:26467025 PMID:28492532 PMID:33451724 PMID:33516529
PM1	Not assessed	Not assessed: no MSH3-approved domain table or validated critical functional-region annotation places p.Arg669 in a PM1-qualifying region.
PM2	Met	Met at supporting: gnomAD v4.1 AF 4.46249e-05 is below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband biallelic observation or confirmed in-trans pathogenic MSH3 variant is documented.	generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002439.5:c.2006G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Arg669Gln). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: zero validated pathogenic or likely pathogenic alternate missense variants at MSH3 residue Arg669 were identified.
PM6	Not assessed	Not assessed: no affected proband with a presumed de novo NM_002439.5:c.2006G>A result and no supporting parental or family evidence is reported.
PP1	Not assessed	Not assessed: no informative affected relatives, non-carriers, meioses, or phenotype-concordant family segregation data are available.
PP2	Not assessed	Not assessed: MSH3 loss-of-function evidence is present, but no gene-specific missense-rate data establish PP2 eligibility.
PP3	Not met	Not met: REVEL score 0.202 is below the PP3 supporting threshold of 0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history sufficiently specific for an MSH3-related disease is documented.	clinvar PMID:24905773 PMID:24929052 PMID:25394175 PMID:33516529
PP5	Not met	Not met: ClinVar reports 0 expert-panel submissions, and no exact-variant Pathogenic or Likely pathogenic expert-panel classification exists.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 4.46249e-05 is far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest gnomAD v4.1 frequency is 4.46249e-05, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but available heterozygotes lack individual phenotype data needed to establish BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated variant-specific assay with controlled, disease-relevant results showing normal MSH3 function was identified.	clinvar PMID:25741868
BS4	Not assessed	Not assessed: no tested affected relatives lacking NM_002439.5:c.2006G>A and no informative non-segregation observation are documented.
BP1	Not assessed	Not assessed: MSH3 loss-of-function evidence alone does not prove that pathogenic missense variants are uncommon enough for BP1.
BP2	Not assessed	Not assessed: no documented cis co-occurrence with a pathogenic or likely pathogenic MSH3 variant is available.	generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002439.5:c.2006G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Arg669Gln). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: REVEL score 0.202 is below the BP4 threshold of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no confirmed alternate molecular or clinical explanation is documented to account for the relevant phenotype independently of this variant.	clinvar oncokb
BP6	Not met	Not met: ClinVar reports 0 expert-panel submissions, so the two single-submitter Likely benign assertions cannot trigger BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002439.5:c.2006G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Arg669Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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.