Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000249.4(MLH1):c.305A>C(p.Glu102Ala) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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. E102D) has been classified as Pathogenic.
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37001053-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 3-37001052-A-C is Pathogenic according to our data. Variant chr3-37001052-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486866.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-37001052-A-C is described in Lovd as [Pathogenic].
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 08, 2018
The c.305A>C variant (also known as p.E102A), located in coding exon 3 of the MLH1 gene, results from an A to C substitution at nucleotide position 305. The glutamic acid at codon 102 is replaced by alanine, an amino acid with dissimilar properties. This alteration was identified in an individual whose family history met Amsterdam I criteria for Lynch syndrome and colorectal tumor showed high microsatellite instability (MSI-H) (Ambry internal data). This alteration was also reported in an individual with a MSI-H colorectal tumor which showed loss of MLH1 and PMS2 protein expression on immunohistochemistry (Nyiraneza C et al. Hum. Pathol., 2011 Dec;42:1897-910). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -