ClinVar Genomic variation as it relates to human health

The MLH1 c.650G>A; p.Arg217His variant (rs762099920), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 220367). This variant is found in the general population with an overall allele frequency of 0.002 % (6 / 282,492 alleles) in the Genome Aggregation Database. The arginine at codon 217is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg217His variant is uncertain at this time.

This missense variant replaces arginine with histidine at codon 217 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/282492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 27149842, 22753075, 28524162, 35402282)

The p.R217H variant (also known as c.650G>A), located in coding exon 8 of the MLH1 gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The MLH1 p.Arg217His variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs762099920) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx and Ambry Genetics), Clinvitae, and in Cosmic (2x found in Large intestine and 1x in Stomach) databases. The variant was identified in control databases in 6 of 276802 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24030 chromosomes (freq: 0.00004), European in 4 of 126314 chromosomes (freq: 0.00003), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg217 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.