14-75048943-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001040108.2(MLH3):c.713A>G(p.Tyr238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.713A>G | p.Tyr238Cys | missense_variant | Exon 2 of 13 | 5 | NM_001040108.2 | ENSP00000348020.2 | ||
MLH3 | ENST00000380968.6 | c.713A>G | p.Tyr238Cys | missense_variant | Exon 2 of 12 | 1 | ENSP00000370355.3 | |||
MLH3 | ENST00000556257.5 | c.713A>G | p.Tyr238Cys | missense_variant | Exon 2 of 7 | 5 | ENSP00000451540.1 | |||
MLH3 | ENST00000553263.1 | c.*226A>G | downstream_gene_variant | 2 | ENSP00000451192.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152260Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249962Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135276
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1460982Hom.: 0 Cov.: 35 AF XY: 0.0000303 AC XY: 22AN XY: 726760
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74392
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Y238C variant (also known as c.713A>G), located in coding exon 1 of the MLH3 gene, results from an A to G substitution at nucleotide position 713. The tyrosine at codon 238 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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
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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 375855). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. This variant is present in population databases (rs144707485, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 238 of the MLH3 protein (p.Tyr238Cys). -
Colorectal cancer Uncertain:1
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 45 year old female with a history of 3-4 colon polyps and a family history of colon cancer. -
MLH3-related disorder Uncertain:1
The MLH3 c.713A>G variant is predicted to result in the amino acid substitution p.Tyr238Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). In ClinVar, this variant has been listed as 'uncertain significance' by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/375855/). 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