rs386810227

Variant names:

• chr19-50417278-CA-TG
• rs386810227
• NM_002691.4:c.3218+9_3218+10delCAinsTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_002691.4(POLD1):​c.3218+9_3218+10delCAinsTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.591
• Publications: 0 publications found

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

POLD1 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 19-50417278-CA-TG is Benign according to our data. Variant chr19-50417278-CA-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3218+9_3218+10delCAinsTG		intron_variant	Intron 26 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3218+9_3218+10delCAinsTG		intron_variant	Intron 26 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.425+9_425+10delCAinsTG		intron_variant	Intron 5 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Benign:1

Aug 27, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLD1 c.3218+9_3218+10delinsTG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was inferred to be at a frequency of 0.0052 in 226738 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 368-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.3218+9_3218+10delinsTG in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. All laboratories classified the variant as benign/likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.3218+9_3218+10delinsTG variant was not identified in the literature nor was it identified in the ClinVar database. The variant was only identified in dbSNP (ID: rs386810227) as "With other allele". The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). However, the POLD1 c.3218+9C>T variant was identified in control databases in 1197 of 231534 chromosomes (10 homozygous) at a frequency of 0.005 and the POLD1 c.3218+10A>G variant was identified in control databases in 10250 of 231916 chromosomes (1374 homozygous) at a frequency of 0.04 (Genome Aggregation Database Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=7/93	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386810227; hg19: chr19-50920535;