rs762525606
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001040108.2(MLH3):āc.2850T>Gā(p.Asn950Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251314Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461814Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727198
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2024 | The p.N950K variant (also known as c.2850T>G), located in coding exon 1 of the MLH3 gene, results from a T to G substitution at nucleotide position 2850. The asparagine at codon 950 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 | Jun 11, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 950 of the MLH3 protein (p.Asn950Lys). This variant is present in population databases (rs762525606, gnomAD 0.004%). 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: 544271). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at