Variant classification summary

NM_001040108.2:c.3488G>A

MLH3 · NP_001035197.1:p.(Gly1163Asp) · NM_001040108.2

GRCh37: chr14:75506696 C>T · GRCh38: chr14:75039993 C>T

Gene: MLH3 Transcript: NM_001040108.2

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Gly1163Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MLH3 c.3488G>A (p.Gly1163Asp; p.G1163D) variant has been reported in ClinVar, where most submissions classify it as benign (6 laboratories) and a minority classify it as uncertain significance (2 laboratories).

2

This variant is common in population databases, with East Asian allele frequencies of 2.83720% in gnomAD v2.1 and 2.24070% in gnomAD v4.1, exceeding the default BA1 threshold of 1% and BS1 threshold of 0.3%.

3

Computational evidence argues against a deleterious effect: SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.113, and BayesDel is -0.258625.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Not met	This variant is a missense substitution, p.(Gly1163Asp), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although gene-level review supports loss of function as a disease mechanism for MLH3, available evidence does not support applying PVS1 to this specific variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified that this exact amino acid change, p.(Gly1163Asp), is caused by a different nucleotide change already established as pathogenic.	clinvar
PS2	Not met	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study of this exact variant was identified, so pathogenic functional evidence could not be assessed.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals compared with controls. No case series or case-control data supporting increased prevalence in disease were identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant does not have evidence of occurring in a well-established mutational hotspot or a clearly defined critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots
PM2	Not met	This variant is not absent or rare in population databases. Its allele frequency is 0.21291% in gnomAD v2.1 and 0.07207% in gnomAD v4.1, both above the default PM2 threshold of 0.1%, and the highest East Asian frequencies are 2.83720% and 2.24070%, respectively.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting.	clinvar
PM4	N/A	This variant is a missense substitution and does not change protein length or involve an in-frame insertion or deletion, so PM4 is not applicable.	clinvar
PM5	Not met	No evidence was identified that a different missense change at codon 1163 is already established as pathogenic.	clinvar
PM6	Not met	No presumed de novo occurrence of this variant without confirmed parentage was identified.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so co-segregation with disease could not be assessed.	clinvar
PP2	Not assessed	No gene-specific evidence was identified showing that pathogenic missense variation is a common mechanism in MLH3 and that benign missense variation is uncommon, so PP2 was not assessed.	clinvar
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625.	spliceai revel bayesdel
PP4	Not assessed	No highly specific phenotype, family history, or tumor profile attributable to this exact variant was identified, so PP4 could not be assessed.	clinvar
PP5	Not met	A pathogenic assertion from a reputable source without accessible supporting evidence was not identified for this variant.	clinvar
BA1	Met	This variant exceeds the default BA1 population threshold of 1%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both above 1%.	gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the default BS1 population threshold of 0.3%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both well above 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Although homozygotes are present in gnomAD, the disease-specific penetrance and inheritance context needed to apply BS2 were not established here, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing normal or near-normal function for this exact variant was identified, so benign functional evidence could not be assessed.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 could not be assessed.	clinvar
BP1	Not assessed	This is a missense variant, but there was not enough gene-specific evidence to conclude that pathogenic variation in MLH3 is predominantly truncating with missense changes generally benign, so BP1 was not assessed.	pvs1_gene_context
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 could not be assessed.	clinvar
BP3	Not assessed	This criterion is intended for in-frame indels in repetitive regions, and no relevant evidence was identified for this missense variant.	clinvar
BP4	Met	Multiple computational results support a benign interpretation. SpliceAI shows no significant splice effect with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625, together arguing against a deleterious protein or splice effect.	spliceai revel bayesdel
BP5	Not assessed	No evidence was identified for an alternate molecular basis explaining the observed phenotype independent of this variant, so BP5 could not be assessed.	clinvar
BP6	Not met	A benign assertion from a reputable source without accessible supporting evidence was not used here because ClinVar submissions are mixed, with benign and uncertain significance classifications present rather than a single clear benign assertion.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is missense, so BP7 is not applicable.	clinvar

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