rs772866061
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001040108.2(MLH3):āc.4301A>Gā(p.Lys1434Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.4301A>G | p.Lys1434Arg | missense_variant | 13/13 | ENST00000355774.7 | NP_001035197.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.4301A>G | p.Lys1434Arg | missense_variant | 13/13 | 5 | NM_001040108.2 | ENSP00000348020 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151576Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251472Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461726Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30AN XY: 727174
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151576Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74080
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2023 | The p.K1434R variant (also known as c.4301A>G), located in coding exon 12 of the MLH3 gene, results from an A to G substitution at nucleotide position 4301. The lysine at codon 1434 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1434 of the MLH3 protein (p.Lys1434Arg). This variant is present in population databases (rs772866061, gnomAD 0.003%). 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: 410888). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
MLH3-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 09, 2024 | The MLH3 c.4301A>G variant is predicted to result in the amino acid substitution p.Lys1434Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410888/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at