Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4BP6_Moderate
The ENST00000413740.2(MLH1):c.1715A>G(p.Asn572Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N572I) has been classified as Uncertain significance.
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 Uncertain_significance. Variant got 1 ACMG points.
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 13 uncertain in ENST00000413740.2
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3033257).
BP6
Variant 3-37050533-A-G is Benign according to our data. Variant chr3-37050533-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1155416.Status of the report is criteria_provided_single_submitter, 1 stars.