ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability <0.001

Converted during submission to Benign.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.0% African chromosomes

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

MLH1: BS1, BS2

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Converted during submission to Benign.

The MLH1 p.Val213Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs2308317) as With Benign ,Uncertain significance allele , ClinVar (classified as benign by InSight, GenDx, Ambry Genetics, Invitae; classified as likely benign by Illumina), Clinvitae (classified as benign by ClinVar), UMD-LSDB (3X as neutral), Insight Colon Cancer Gene Variant Database (8X class 1), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 733(11 homozygous) of 276886 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 671 of 24030 chromosomes (freq: 0.028). Functional analysis of human MLH1 variants using yeast identify the variant has normal EXO1-binding, normal PMS2-binding and normal MMR function (Kondo 2003, Takahashi 2007). The variant functioned like the WT MLH1 in all of the assays in Raevaara (2005) with normal MMR function, normal nuclear concentration of MLH1 and normal nuclear concentration of the MLH1-PMS2 heterodimer. In addition, the variant has no effect on splicing in the pCAS ExVivo SplicingAssay (Tournier 2008) and concordant with patient RNA. The p.Val213 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. The variant is located with the Histidine kinase-like ATPase, ATP-binding domain DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.