rs748417604
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate
The NM_000249.4(MLH1):c.454G>A(p.Val152Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V152G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.454G>A | p.Val152Met | missense_variant, splice_region_variant | 6/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.454G>A | p.Val152Met | missense_variant, splice_region_variant | 6/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251266Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135818
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459994Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726452
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 05, 2023 | This missense variant replaces valine with methionine at codon 152 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2023 | The p.V152M variant (also known as c.454G>A), located in coding exon 6 of the MLH1 gene, results from a G to A substitution at nucleotide position 454. The valine at codon 152 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data). In one study, this variant was observed in 1/626 Northern European patients with colorectal cancer diagnosed before age 56, who had at least one first-degree relative with colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces valine with methionine at codon 152 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809), esophageal squamous cell carcinoma (PMID: 30833958), or breast cancer (PMID 34359559). This variant has been identified in 2/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2018 | This variant is denoted MLH1 c.454G>A at the cDNA level, p.Val152Met (V152M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been observed in at least one individual with a personal and family history of colorectal cancer (Chubb 2015). MLH1 Val152Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val152Met occurs at a position that is conserved across species and is located within the N-terminal ATPase domain (Anderson 2012). Protein based in silico analyses predict that this variant is probably damaging to protein structure and function while splicing based models predict this variant to either weaken or destroy the natural splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MLH1 Val152Met is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Muir-Torré syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 13, 2023 | The MLH1 c.454G>A variant is classified as VUS (PS4_Supporting, PM2, PP3) The MLH1 c.454G>A variant is located in a splice region. The MLH1 c.454G>A variant is a single nucleotide change in exon 6/19 of the MLH1 gene, which is predicted to change the amino acid valine at position 152 in the protein to methionine. The variant has been reported in a patient with esophageal cancer and another with colon cancer (PMID:25559809, PMID:30833958) (PS4_Supporting). This variant is absent from population databases (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs748417604) and in the HGMD database (CM1913018). It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 184683). - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the MLH1 protein (p.Val152Met). This variant is present in population databases (rs748417604, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer and esophageal cancer (PMID: 25559809, 30833958). ClinVar contains an entry for this variant (Variation ID: 184683). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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