Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.806C>G(p.Ser269Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S269S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37017521-C-G is Pathogenic according to our data. Variant chr3-37017521-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17098.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37017521-C-G is described in Lovd as [Pathogenic].
This sequence change creates a premature translational stop signal (p.Ser269*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Lynch syndrome (PMID: 15571801, 12547705, 18625694, 17453009, 9311737). ClinVar contains an entry for this variant (Variation ID: 17098). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. -
The p.S269* pathogenic mutation (also known as c.806C>G), located in coding exon 10 of the MLH1 gene, results from a C to G substitution at nucleotide position 806. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals diagnosed with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Overbeek LI et al. Br. J. Cancer 2007 May;96:1605-12), including several patients whose tumors demonstrated high microsatellite instability and loss of MLH1 staining on immunohistochemistry (IHC) (van Puijenbroek M et al. Fam. Cancer 2008 Apr;7:319-30; Bosse T et al. Mod Pathol, 2013 Nov;26:1525-35; Post CCB et al. J Natl Cancer Inst, 2021 Mar). This mutation has also been reported as homozygous in a patient with colon cancer diagnosed at age 22 (Rey JM et al. Cancer Genet Cytogenet, 2004 Dec;155:149-51). Of note, this alteration is also designated as 269 TCA>TGA, S269X, and p.Ser269X in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -