Submissions for variant NM_002691.4(POLD1):c.3271G>A (p.Asp1091Asn)

gnomAD frequency: 0.00009  dbSNP: rs946088822

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468092	SCV000547542	uncertain significance	Colorectal cancer, susceptibility to, 10	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1091 of the POLD1 protein (p.Asp1091Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407995). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV001653826	SCV001871154	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant; This variant is associated with the following publications: (PMID: 29056344)
Mendelics	RCV004701499	SCV002519159	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Ambry Genetics	RCV002323712	SCV002610896	likely benign	Hereditary cancer-predisposing syndrome	2024-03-07	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV005018769	SCV005650328	uncertain significance	Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome; Immunodeficiency 120	2024-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737518	SCV005352141	uncertain significance	POLD1-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The POLD1 c.3271G>A variant is predicted to result in the amino acid substitution p.Asp1091Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating it is rare. In ClinVar, this variant has been classified as likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/RCV000468092.6/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.