ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.1061C>T (p.Ala354Val) (rs140990974)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232660 SCV000287499 likely benign not provided 2019-02-11 criteria provided, single submitter clinical testing
GeneDx RCV000481032 SCV000567056 uncertain significance not specified 2017-07-11 criteria provided, single submitter clinical testing This variant is denoted POLD1 c.1061C>T at the cDNA level, p.Ala354Val (A354V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLD1 Ala354Val was observed with an allele frequency of 0.3% in the African populations in 1000 Genomes. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. POLD1 Ala354Val occurs at a position where amino acids with properties similar to Alanine are tolerated across species and is located in the exonuclease domain (Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLD1 Ala354Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575879 SCV000670988 likely benign Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000481032 SCV000918077 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: POLD1 c.1061C>T (p.Ala354Val) results in a non-conservative amino acid change located in the exonuclease domain (IPR006133) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 191816 control chromosomes (gnomAD). The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1061C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign (2x), VUS (2x)). Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics RCV000575879 SCV000788123 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-03 no assertion criteria provided clinical testing

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