NM_001040108.2:c.20T>A

MLH3 · NP_001035197.1:p.(Val7Asp) · NM_001040108.2

GRCh37: chr14:75516339 A>T · GRCh38: chr14:75049636 A>T

Gene: MLH3 Transcript: NM_001040108.2

Final call

VUS

PM2 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Val7Asp)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001040108.2:c.20T>A (p.Val7Asp) is a missense variant in exon 2 of MLH3, a DNA mismatch repair gene associated with autosomal dominant Lynch syndrome and autosomal recessive polyposis predisposition.

This variant is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2 at a supporting strength level.

Multiple computational predictors do not support a deleterious effect: REVEL score is 0.384 (intermediate), BayesDel is −0.281 (benign-leaning), and SpliceAI predicts no splice impact (max delta 0.00). PP3 is not met.

The variant has been reported once in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics; Variation ID 1785889); no pathogenic or benign consensus exists.

No variant-specific functional studies, case-control data, cosegregation evidence, or de novo observations were identified for this variant in the available evidence sources.

The PVS1 criterion is not applicable as this is a missense change (p.Val7Asp) that does not meet the ClinGen SVI PVS1 null-variant criteria (PMC6185798).

The variant has been observed once in a somatic cancer context (COSMIC COSV53136280), which is not directly informative for germline pathogenicity classification.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_001040108.2:c.20T>A is a missense variant (p.Val7Asp) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No established pathogenic variant with the same amino acid change (p.Val7Asp) at this residue has been identified in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence of NM_001040108.2:c.20T>A has been reported in a patient with confirmed parental relationships.
PS3	Not met	No well-established functional studies demonstrate a deleterious effect of p.Val7Asp on MLH3 protein function. OncoKB did not identify variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control or cohort data demonstrate enrichment of NM_001040108.2:c.20T>A in affected individuals compared to controls.
PS5	Not met	ClinVar classification is Uncertain significance (single submitter, Ambry Genetics); no reputable source asserts pathogenicity for this variant.	clinvar
PM1	Not met	The variant lies at residue 7 in MLH3, which is not within a statistically significant cancer hotspot and does not fall within a well-characterized critical functional domain without benign variation.
PM2	Met	NM_001040108.2:c.20T>A is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold for a variant with allele frequency below 0.1% in controls.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue missense comparator variant with a confirmed pathogenic classification could be identified. Automated PM5 candidate harvesting was unable to confirm eligible comparators.
PM6	Not met	No assumed de novo without paternity/maternity confirmation has been reported for NM_001040108.2:c.20T>A.
PP1	Not met	No cosegregation data with disease has been reported for this variant in affected families.
PP2	Not assessed	Insufficient gene-level constraint data (missense Z-score, benign missense rate) available to determine whether MLH3 has a low rate of benign missense variation that would qualify for PP2. HCI prior lookup did not return a score for MLH3.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.384 (below typical pathogenic threshold), BayesDel score -0.281 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splice impact).	revel bayesdel spliceai
PP4	Not met	No specific phenotype or family history data are available for the individual harboring NM_001040108.2:c.20T>A to assess phenotypic specificity for MLH3-associated disease.
PP5	Not met	No reputable source (e.g., expert panel, clinical laboratory consensus) reports NM_001040108.2:c.20T>A as pathogenic. The sole ClinVar submission classifies it as Uncertain significance.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in a homozygous state in healthy adults, nor has it been observed at a frequency inconsistent with MLH3-associated disease penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a neutral or non-deleterious effect of p.Val7Asp on MLH3 protein function. OncoKB did not identify variant-specific functional evidence.	oncokb
BS4	Not met	No non-segregation data with disease in affected families is available for NM_001040108.2:c.20T>A.
BP1	N/A	Both missense and truncating variants in MLH3 are known to be associated with Lynch syndrome and polyposis predisposition; MLH3 is not a gene for which primarily truncating variants cause disease.
BP2	Not met	No evidence that NM_001040108.2:c.20T>A has been observed in trans with a known pathogenic MLH3 variant in the context of a fully penetrant dominant disorder.
BP4	Not met	Computational evidence is mixed and does not consistently support a non-deleterious effect: BayesDel predicts benign (-0.281), but REVEL is intermediate (0.384) and SpliceAI is neutral (max delta 0.00). Multiple lines of computational evidence do not converge on a benign prediction.	revel bayesdel spliceai
BP5	Not met	No case has been identified where NM_001040108.2:c.20T>A was found in a patient with an alternate molecular basis for MLH3-associated disease.
BP6	Not met	No reputable source reports NM_001040108.2:c.20T>A as benign or likely benign. ClinVar classification is Uncertain significance (single submitter).	clinvar
BP7	N/A	NM_001040108.2:c.20T>A is a missense variant (p.Val7Asp), not a synonymous variant. SpliceAI predicts no splice impact (max delta 0.00), but BP7 is reserved for synonymous variants without predicted splice effect.	spliceai

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