NM_001040108.2:c.1910G>A

MLH3 · NP_001035197.1:p.(Arg637His) · NM_001040108.2

GRCh37: chr14:75514449 C>T · GRCh38: chr14:75047746 C>T

Gene: MLH3 Transcript: NM_001040108.2

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Arg637His)

gnomAD AF

1.4869004074107116e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MLH3 c.1910G>A (p.Arg637His, p.R637H) variant has been reported in ClinVar, where current submissions classify it as a variant of uncertain significance.

This variant is rare in population databases, with a total allele frequency of 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, and it is absent from gnomAD-Canada v1.0.

Available computational evidence does not support a damaging effect: REVEL is 0.103, BayesDel is -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	This is a missense variant, not a nonsense, frameshift, or canonical +/-1/2 splice variant, so the generic PVS1 loss-of-function framework does not apply even though MLH3 loss of function is considered a relevant disease mechanism at the gene level.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that a different nucleotide change causing the same Arg637His protein effect has already been established as pathogenic or likely pathogenic.	clinvar
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant.	clinvar
PS3	Not assessed	No published well-established functional study demonstrating a damaging effect of this specific variant was identified.	oncokb
PS4	Not assessed	No case-control enrichment data or multiple independent affected observations sufficient to show increased prevalence in affected individuals were identified for this variant.	clinvar PMID:34043773 PMID:28492532
PM1	Not met	This variant has not been identified in a well-established functional domain or statistically significant hotspot, and Cancer Hotspots did not show a significant hotspot signal at residue R637.	hotspots
PM2	Met	Population frequency is below the 0.1% rarity threshold used for generic ACMG review. The variant is present at 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, with no homozygotes in either dataset, and it is absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.	clinvar
PM4	N/A	This is a missense substitution and does not produce a protein length change or in-frame insertion/deletion.
PM5	N/A	PM5 was not applied because classic same-residue PM5 semantics could not be confirmed safely for this framework, and no qualifying pathogenic same-residue comparator variants were identified.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence does not establish that MLH3 missense variation in general is a common mechanism of disease with sufficiently low benign missense background to support PP2.	final_classification_framework
PP3	Not met	Available computational evidence does not support a damaging effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.	revel bayesdel spliceai
PP4	Not assessed	No phenotype, family history, or tumor-feature evidence specific enough to support a highly characteristic disease presentation was identified for this variant.	clinvar PMID:34043773
PP5	N/A	Reputable-source assertions alone were not used because the available ClinVar submissions classify this variant as uncertain significance and do not provide independent evidence sufficient for PP5.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold of greater than 1%. The highest observed population frequency is 0.02288% in gnomAD v2.1 South Asian samples, which is far below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the benign strong threshold of greater than 0.3%. The highest observed population frequency is 0.02288% in gnomAD v2.1 South Asian samples, which is below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a context sufficient to establish BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal or near-normal function for this specific variant was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.	clinvar
BP1	Not assessed	Available evidence does not establish that missense variation in MLH3 is a clearly low-risk mechanism relative to truncating variants, so BP1 was not applied.	final_classification_framework
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.	clinvar
BP3	N/A	This is a single amino-acid substitution and not an in-frame insertion/deletion in a repetitive region without known function.
BP4	Met	Multiple computational findings support no deleterious effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular cause explaining the reported phenotype was identified, so BP5 could not be assessed.	clinvar
BP6	N/A	Reputable-source benign assertions alone were not used because the available ClinVar submissions classify this variant as uncertain significance, not likely benign or benign.	clinvar
BP7	N/A	BP7 does not apply because this is not a synonymous or deep intronic variant.

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