ClinVar Genomic variation as it relates to human health

MAF >1%

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.

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.

The MSH2 p.Phe922= variant was identified in 1 of 70 proband chromosomes (frequency: 0.01) from Portuguese individuals or families with HNPCC and was not identified in 400 control chromosomes from healthy individuals (Isidro_2003_14517962). In addition, mRNA analysis showed the variant yielded no alternative transcripts, and segregation studies showed the variant was found in both affected and unaffected family members (Isidro_2003_14517962). The variant was also identified in dbSNP (ID: rs55859129) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (2014); submitters: benign by InSIGHT, Invitae, Ambry Genetics and Mayo Clinic, and likely benign by Illumina), Clinvitae (4x), UMD-LSDB (4x as neutral, co-occurring with a pathogenic MSH6 variant (c.2150_2153delTCAG (p.Val717AlafsX18)), Insight Colon Cancer Gene Variant Database (3x as class 1), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database, and was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1074 (14 homozygous) of 274470 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 989 (14 homozygous) of 23868 chromosomes (freq: 0.04), Other in 7 of 6412 chromosomes (freq: 0.001), Latino in 71 of 34118 chromosomes (freq: 0.002), European Non-Finnish in 7 of 125698 chromosomes (freq: 0.00006), while not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Phe922= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 this variant meets our laboratory's criteria to be classified as benign.