Submissions for variant NM_002691.4(POLD1):c.883G>A (p.Val295Met)

gnomAD frequency: 0.00060  dbSNP: rs199545019

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000990252	SCV000287655	likely benign	Colorectal cancer, susceptibility to, 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000236306	SCV000293151	uncertain significance	not specified	2017-03-15	criteria provided, single submitter	clinical testing	This variant is denoted POLD1 c.883G>A at the cDNA level, p.Val295Met (V295M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). Bellido et al. (2015) identified this variant in two kindreds characterized by familial or early-onset mismatch repair proficient colorectal cancer and/or APC and MUTYH-negative polyposes. In one family POLD1 Val295Met was present in both a woman with early-onset colorectal cancer and her mother, who was diagnosed with colorectal cancer at age 70. In the second family, POLD1 Val296Met was observed in trans with a second POLD1 missense variant, Asp316Gly, which the authors interpreted as pathogenic. While the mother in this kindred, who was affected with breast and endometrial cancer, harbored both variants, a daughter affected with both colorectal and endometrial cancer only inherited POLD1 Asp316Gly. POLD1 Val295Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. POLD1 Val295Met occurs at a position that is conserved in mammals and is not located in a known functional domain (Tahirov 2009, 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 Val295Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509515	SCV000601960	benign	not provided	2019-04-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891813	SCV000806567	likely benign	POLD1-related condition	2022-06-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mendelics	RCV000990252	SCV001141137	likely benign	Colorectal cancer, susceptibility to, 10	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000509515	SCV001152018	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	POLD1: BP4, BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236306	SCV001519529	likely benign	not specified	2021-03-07	criteria provided, single submitter	clinical testing	Variant summary: POLD1 c.883G>A (p.Val295Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 218624 control chromosomes. The observed variant frequency is approximately 40 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. c.883G>A has been reported in the literature as a VUS in at-least two families with a history of cancers but no conclusive co-segregation with disease (example, Bellido_2016, Buchanan_2018) These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 some citing overlapping evidence utilized in the context of this evaluation (likely benign, n=2; benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000236306	SCV002065987	likely benign	not specified	2021-09-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.883G>A, in exon 8 that results in an amino acid change, p.Val295Met. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a population frequency of 0.14% in Ashkenazi Jewish subpopulation (dbSNP rs199545019). The p.Val295Met change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is known to be functional. The p.Val295Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Val295Met change remains unknown at this time.
Sema4, Sema4	RCV002257546	SCV002534709	likely benign	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236306	SCV002551891	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000509515	SCV000606987	not provided	not provided		no assertion provided	phenotyping only	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356392	SCV001551548	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLD1 p.Val295Met variant was identified in 2 of 1058 proband chromosomes (frequency: 0.002) from individuals or families with early-onset nonpolyposis CRC (Bellido 2016). The variant was also identified in dbSNP (ID: rs199545019) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae; as uncertain significance by GeneDx and two clinical laboratories). The variant was identified in control databases in 120 of 243858 chromosomes at a frequency of 0.0005 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: Other in 9 of 5878 chromosomes (freq: 0.002), Latino in 35 of 30486 chromosomes (freq: 0.001), European in 52 of 109472 chromosomes (freq: 0.0005), Ashkenazi Jewish in 14 of 9360 chromosomes (freq: 0.002), and South Asian in 10 of 28292 chromosomes (freq: 0.0004); it was not observed in the African, East Asian, or Finnish populations. The p.Val295 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics, Academic Medical Center	RCV000509515	SCV001920022	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000509515	SCV001931939	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000509515	SCV001953786	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000509515	SCV001973450	likely benign	not provided		no assertion criteria provided	clinical testing