rs1004768761
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001040108.2(MLH3):c.962T>C(p.Met321Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
MLH3
NM_001040108.2 missense
NM_001040108.2 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.962T>C | p.Met321Thr | missense_variant | 2/13 | ENST00000355774.7 | NP_001035197.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.962T>C | p.Met321Thr | missense_variant | 2/13 | 5 | NM_001040108.2 | ENSP00000348020.2 | ||
MLH3 | ENST00000380968.6 | c.962T>C | p.Met321Thr | missense_variant | 2/12 | 1 | ENSP00000370355.3 | |||
MLH3 | ENST00000556257.5 | c.962T>C | p.Met321Thr | missense_variant | 2/7 | 5 | ENSP00000451540.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251022Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461864Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727224
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2024 | The p.M321T variant (also known as c.962T>C), located in coding exon 1 of the MLH3 gene, results from a T to C substitution at nucleotide position 962. The methionine at codon 321 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 321 of the MLH3 protein (p.Met321Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 581825). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 28, 2023 | The MLH3 c.962T>C; p.Met321Thr variant (rs1004768761), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 581825). This variant is only found on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.626). Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Uncertain
Sift
Benign
T;.;D;T
Sift4G
Uncertain
D;D;D;D
Polyphen
P;B;.;P
Vest4
MutPred
Gain of catalytic residue at V319 (P = 0.0159);Gain of catalytic residue at V319 (P = 0.0159);Gain of catalytic residue at V319 (P = 0.0159);Gain of catalytic residue at V319 (P = 0.0159);
MVP
MPC
ClinPred
T
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at