Submissions for variant NM_002691.4(POLD1):c.2987C>T (p.Thr996Met)

gnomAD frequency: 0.00010  dbSNP: rs918661445

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480642	SCV000571948	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35534704, 35264596)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558091	SCV000646625	uncertain significance	Colorectal cancer, susceptibility to, 10	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 996 of the POLD1 protein (p.Thr996Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 422465). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV000709591	SCV000839447	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225730	SCV003807860	uncertain significance	Mandibular hypoplasia-deafness-progeroid syndrome	2022-06-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4 supporting
Ambry Genetics	RCV003168965	SCV003912615	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-26	criteria provided, single submitter	clinical testing	The p.T996M variant (also known as c.2987C>T), located in coding exon 23 of the POLD1 gene, results from a C to T substitution at nucleotide position 2987. The threonine at codon 996 is replaced by methionine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005018812	SCV005650323	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-04-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737553	SCV005351286	uncertain significance	POLD1-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The POLD1 c.2987C>T variant is predicted to result in the amino acid substitution p.Thr996Met. This variant has been identified in patient with breast cancer and an individual with a family history of breast cancer (Supp. Table 3, Guindalini et al. 2022. PubMed ID: 35264596; Supp. Table 3, de Oliveira et al. 2022. PubMed ID: 35534704). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD and is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/422465/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.