ClinVar Genomic variation as it relates to human health

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: This variant is present in ExAC with a MaxMAF of 0.242% (35 South Asian and 150 European alleles) and 2% in gnomAD (207 Ashkenazi alleles - too high for disease prevalence). It is classified in ClinVar with 1 star as Likely benign by 2 submitters (Invitae, Vantari) and as VUS by GeneDx.

This variant is associated with the following publications: (PMID: 25986922, 25822476, 23376243, 27153395, 30086056)

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

This alteration is classified as likely 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.

POLD1: BS2

The POLD1 p.Val759Ile variant was identified in 4 of 84 proband chromosomes (frequency: 0.0476) from individuals or families with early-onset colon cancer (Rosner_2015). The variant was also identified in dbSNP (ID: rs145473716) as “With other allele”, ClinVar (as benign by Invitae, as likely benign by Vantari Genetics, GeneDx, Partners Health Care Personalized Medicine, Quest Diagnostics, and Ambry Genetics, and as uncertain significance by Counsyl), Clinvitae (3x), and Cosmic (in somatic tumours in the large intestine and central nervous system). The variant was not identified in the MutDB database. The variant was identified in control databases in 461 of 273426 chromosomes (8 homozygous) at a frequency of 0.001686 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 1 of 24014 chromosomes (freq: 0.000042), Other in 12 of 6404 chromosomes (freq: 0.001874), Latino in 21 of 34128 chromosomes (freq: 0.000615), European (Non-Finnish) in 116 of 125376 chromosomes (freq: 0.000925), Ashkenazi Jewish in 209 of 9996 chromosomes (freq: 0.02091), East Asian in 19 of 18792 chromosomes (freq: 0.001011), and South Asian in 83 of 30524 chromosomes (freq: 0.002719), while the variant was not observed in the European (Finnish) populations. Interestingly, in a study of genetic variants that cause longevity, the p.Val759Ile variant was found in 14 controls and 17 centenarians (individuals over 105 years old) (Han_2013_23376243). The p.Val759 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 this variant meets our laboratory's criteria to be classified as benign.