ClinVar Genomic variation as it relates to human health

MAF >1% in a specific ethnic group (European American)

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.

PMS2: BS1, BS2

Variant summary: The PMS2 c.52A>G (p.Ile18Val) variant located in the Histidine kinase-like ATPase, C-terminal domain of the protein (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, a functional study indicates the variant does not affect MMR activity (Drost_2013. This variant was found in 2457/271244 control chromosomes (gnomAD) including 22 homozygotes at a frequency of 0.0090519, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. However, this observation needs to be cautiously considered because the sequencing technology (exome and genome sequencing) used cannot rule out the fact that the pseudogene could have been amplified. Several publications have cited the variant in affected individuals with Lynch Syndrome or related disorders, including reports of lack of cosegregation with disease in multiple families (Leongamornlert_2014 and Hendriks_2006). This variant also co-occurred with another pathogenic variant in a CRC patient and a suspected LS patient (Haraldsdottir_2017 and van der Klift_2016). In addition, in multiple internal LCA samples this variant was found to co-occur with another pathogenic or likely pathogenic variants such as PMS2 c.137G>T (p.Ser46Ile), MSH6 c.1634_1637delAAGA (p.Lys545fsX25), BRCA2 c.4647_4650delAGAG (p.Lys1549fsX18) MUTYH c.933+3A>C, MSH2 c.2038C>T (p.Arg680X) and PMS2 c.251-2A>T and MLH1 c.955G>T (p.Glu319X). Furthermore, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as likely benign/benign. Therefore due to the lack of cosegregation with disease, multiple co-occurrences with a pathogenic/likely pathogenic variant, and multiple clinical diagnostic laboratories classifying the variant as "likely benign/benign," the variant of interest has been 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.

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.

PMS2, EXON2, c.52A>G, p.Ile18Val, Heterozygous, Benign The PMS2 p.Ile18Val variant was identified in 11 of 1400 proband chromosomes (frequency: 0.008) from individuals or families with colorectal cancer, prostate cancer, or common variable immunodeficiency disorder and was present in 1 of 1552 control chromosomes (frequency: 0.0006) from healthy individuals (Clendenning 2006, Hendriks 2006, Van Schouwenburg 2015, van der Klift 2016, Leongamornlert 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs63750123) as "With other allele", and ClinVar (classified as benign by fifteen submitters; as likely benign by six submitters). The variant was identified in control databases in 2457 of 271244 chromosomes (22 homozygous) at a frequency of 0.009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 44 of 22858 chromosomes (freq: 0.002), Other in 50 of 6380 chromosomes (freq: 0.008), Latino in 65 of 34296 chromosomes (freq: 0.002), European in 1387 of 122680 chromosomes (freq: 0.01), Ashkenazi Jewish in 5 of 9990 chromosomes (freq: 0.0005), Finnish in 811 of 25762 chromosomes (freq: 0.03), and South Asian in 95 of 30546 chromosomes (freq: 0.003); it was not observed in the East Asian population. The p.Ile18 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, the variant demonstrated repair efficiency similar to wild type and repair-proficient controls (Drost 2013). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. Assessment Date: 2019/07/22 References (PMIDs): 16619239, 24027009, 16472587, 26122175, 27435373, 24556621, 24728327

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.