MLH1 c.1977A>G, p.Arg659=
NM_000249.4:c.1977A>G
Likely Benign
NM_000249.4:c.1977A>G is a synonymous MLH1 variant absent from population databases, with computational evidence (SpliceAI) indicating no splicing impact, and reported as benign by reputable sources. Three supporting benign criteria (PM2, BP4, BP6) yield a final classification of Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
MLH1
Transcript
NM_000249.4
MANE Select
Total Exons
19
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000249.3 | RefSeq Select | 19 exons | Forward |
| NM_000249.2 | Alternative | 19 exons | Forward |
Variant Details
HGVS Notation
NM_000249.4:c.1977A>G
Protein Change
R659=
Location
Exon 17
(Exon 17 of 19)
5'Exon Structure (19 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000249.4
Genome Browser
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HGVS InputNM_000249:c.1977A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.67
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) at or before codon 753 in MLH1...". The evidence for this variant shows: NM_000249.4:c.1977A>G is a synonymous variant not introducing a PTC or affecting canonical splice sites. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic...". The evidence for this variant shows: NM_000249.4:c.1977A>G is synonymous and does not change the amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: ≥4 de novo points...". The evidence for this variant shows: no de novo occurrence data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls.". The evidence for this variant shows: no case-control or segregation data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Moderate: Located in a mutational hot spot and/or critical and well-established functional domain...without benign variation.". The evidence for this variant shows: NM_000249.4:c.1977A>G is a synonymous change not located in a known functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.". The evidence for this variant shows: not found in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Very Strong: ≥4 points for recessive disease alleles in trans; Strong: ≥2 and <4 points; Moderate: ≥1 and <2 points...". The evidence for this variant shows: no evidence of in trans occurrences in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes as a result of in-frame deletions/insertions in a non-repeat region... or stop-loss variants.". The evidence for this variant shows: no change in protein length (synonymous). Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change was classified as Pathogenic...". The evidence for this variant shows: NM_000249.4:c.1977A>G is synonymous, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting: 0.5 de novo points...". The evidence for this variant shows: no unconfirmed de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Strong: Co-segregation with disease in pedigrees with a combined Bayes LR >18.7...". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene that has a low rate of benign missense variation...". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: Predicted splice defect for non-canonical splice nucleotides using SpliceAI delta score ≥0.2...". The evidence for this variant shows: SpliceAI delta score = 0.0, predicting no splice impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Strong: ≥3 independent CRC/Endometrial MSI-H tumors with loss of MMR expression...". The evidence for this variant shows: no tumor phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source recently reports variant as pathogenic, but evidence is not available.". The evidence for this variant shows: sources report benign classification, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: GnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%)...". The evidence for this variant shows: not present in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%)...". The evidence for this variant shows: absent from gnomAD, no elevated frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: Co-occurrence in trans with a known pathogenic variant in the same gene in a patient with LS cancer above median age...". The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Synonymous substitutions with no associated mRNA aberration as determined by laboratory assays...". The evidence for this variant shows: no laboratory mRNA assay data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong: Lack of co-segregation with disease in pedigrees with a combined Bayes LR <0.05...". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in a gene for which primarily truncating variants cause disease.". The evidence for this variant shows: variant is synonymous, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant in a dominant gene...". The evidence for this variant shows: no in trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame deletions/insertions in repetitive regions...". The evidence for this variant shows: it is a single-nucleotide change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1.". The evidence for this variant shows: SpliceAI delta scores are 0.0, indicating no predicted splice impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting: Tumors with MSS and/or no loss of MMR protein expression inconsistent with gene variation...". The evidence for this variant shows: no tumor phenotype data. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory.". The evidence for this variant shows: ClinVar entries report this variant as Likely benign and Benign from reputable clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: A synonymous variant at or beyond -21/+7 exonic positions with no predicted splice impact.". The evidence for this variant shows: genomic coordinates relative to exon boundaries are not provided, so distance to splice sites cannot be confirmed. Therefore, this criterion is not applied.