ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability <0.001

Converted during submission to Benign.

Variant summary: The c.1168C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 229/123604 control chromosomes (2 homozygotes) at a frequency of 0.0018527. The frequency of this variant in East Asian control population is 0.0217, which is about 38 times of the maximal expected frequency of a pathogenic allele (0.0005683), suggesting this variant is benign. This variant has been reported in a large number of patients with LS or endometrial cancer. Two co-occurrences with a pathogenic variant (MLH1, c.2157dup, p.Val720Cysfs*3 and MSH2 c.196-187dupG, respectively) were reported, along with a reported lack of co-segregation with the disease (Okamura_1998). Multiple functional studies showed that MSH2 p.L390F has similar activity to wild-type MSH2. In addition, multiple clinical laboratories/reputable databases classified this variant as benign. Taken together, this variant was classified as benign.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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: 2.1% in East Asian population with 2 homozygotes.

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.

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 Uncertain significance.

The MSH2 p.Leu390Phe variant was identified in 12 of 952 proband chromosomes (frequency: 0.013) from individuals or families with colorectal cancer (Jin 2008, Lee 2005, Wei 2011, Yap 2009, Zhang 2006) and was present in 1 of 220 control chromosomes (frequency: 0.005) from healthy individuals (Zhang 2006). The variant was also identified in dbSNP (ID: rs17224367) as With other allele, ClinVar (classified as benign by InSight, Emory Genetics, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Illumina, LMMPHCPM; classified as uncertain significance by BLDSNIH), Clinvitae (classified as benign by ClinVar, Invitae, EmvClass; classified as uncertain significance by ClinVar), MutDB , UMD-LSDB (2X classified as neutral), Insight Colon Cancer Gene Variant Database (44X classified as class 1), Zhejiang Colon Cancer Database (7X ), Mismatch Repair Genes Variant Database, databases. The variant was not identified in Cosmic, Insight Hereditary Tumors Database, databases. In UMD the variant was identified with a co-occurring pathogenic MLH1 variant (c.304G>A (p.Glu102Lys)), increasing the likelihood that the p.Leu390Phe variant does not have clinical significance. The variant was identified in control databases in 402(4 homozygous) of 277162 chromosomes at a frequency of 0.00145 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu390 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 DNA mismatch repair protein MutS, core DNA mismatch repair protein, MSH2 functional domains, increasing the likelihood that it may have clinical significance. Functional study of MSH2 on the corresponding yeast allele L402 demonstrated no reduction in steady-state levels of MSH2 and positive interaction with all MSH2 partners (Gammie 2007). The variant was also found co-occurring with pathogenic mutation MLH1 variant c.2157dupT (Wei 2011). However, study by Fan (2005) provides strong molecular epidemiologic, structural, bioinformatic, and functional evidence that MSH2 c.1168C>T (p.Leu390Phe) underlies a newly identified phenotype relevant to young sporadic CRC or GC. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.