Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_ModeratePP5_Moderate
The NM_000249(MLH1):c.350C>A(p.Thr117Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T117M) has been classified as Pathogenic.
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
GnomAD3 genomesCov.: 33
Submissions by phenotype
Hereditary cancer-predisposing syndrome
|Likely pathogenic, criteria provided, single submitter||clinical testing||Ambry Genetics||Feb 19, 2019||The p.T117K variant (also known as c.350C>A), located in coding exon 4 of the MLH1 gene, results from a C to A substitution at nucleotide position 350. The threonine at codon 117 is replaced by lysine, an amino acid with similar properties. This variant has been identified in an individual whose family history was suggestive of hereditary non-polyposis colorectal cancer (HNPCC) syndrome (Ambry internal data). Another alteration at the same position, p.T117R, has been reported to decrease MMR activity and reduce MLH1 and PMS2 expression (Takahashi M et al. Cancer Res. 2007; 67:4595-604). MLH1 p.T117R has also been reported in multiple families affected with colon cancer meeting Amsterdam or Bethesda diagnostic criteria for HNPCC syndrome (Buerstedde JM et al J. Med. Genet. 1995;32:909-12; Ellison A et al Hum Mol Genet. 2001 Sep 1;10(18):1889-900; Heinimann K et al Cancer. 1999 Jun 15;85(12):2512-8, Hardt K et al. Fam. Cancer 2011; 10:273-84). Based on an internal structural assessment, the p.T117K variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -|
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