Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4
The NM_000251.3(MSH2):c.12G>C(p.Gln4His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4K) has been classified as Uncertain significance.
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47403202-AG-C is described in ClinVar as [Pathogenic]. Clinvar id is 569035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.39226335).