rs1040524947

chr19-50402124-A-Cchr19-50402124-A-Gchr19-50402124-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_002691.4(POLD1):c.589A>C(p.Ser197Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000373 in 1,609,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S197N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense, splice_region
• Scores: Splicing: ADA: 0.2665
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 19-50402124-A-C is Benign according to our data. Variant chr19-50402124-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537130.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.589A>C	p.Ser197Arg	missense_variant, splice_region_variant	5/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.589A>C	p.Ser197Arg	missense_variant, splice_region_variant	5/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457792 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 197 of the POLD1 protein (p.Ser197Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with colon polyps and breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 537130). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Familial colorectal cancer Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

May 09, 2018

The POLD1 variant designated as NM_002878.3:c.394G>A (p.Val132Ile) is classified as likely benign. In one observed family, a family with the variant had colon polyps that did not show the molecular ultramutation phenotype that is the signature of pathogenic POLD1 mutations (Briggs et al, 2013, PMID: 23447401). This variant is not in the POLD1 exonuclease domain and is unlikely to cause increased cancer risk, as only POLD1 variants that alter exonuclease activity have been documented to be associated with colon and endometrial cancer risk. Additionally, in the same family, in the POLD1 variant often co-occurs with a likely-pathogenic mutation in the CHEK2 gene (p.R145W). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D;.;.;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.77	P;.;.;.;P
Vest4		0.70
MutPred		0.60		Loss of phosphorylation at S197 (P = 0.0561);Loss of phosphorylation at S197 (P = 0.0561);Loss of phosphorylation at S197 (P = 0.0561);Loss of phosphorylation at S197 (P = 0.0561);Loss of phosphorylation at S197 (P = 0.0561);
MVP		0.73
MPC		0.29
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1040524947; hg19: chr19-50905381;