12-132641747-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_006231.4(POLE):c.5278G>A(p.Val1760Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000608 in 1,612,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V1760A) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5278G>A | p.Val1760Met | missense_variant | 39/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5278G>A | p.Val1760Met | missense_variant | 39/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000881 AC: 22AN: 249576Hom.: 0 AF XY: 0.0000740 AC XY: 10AN XY: 135074
GnomAD4 exome AF: 0.0000582 AC: 85AN: 1459748Hom.: 0 Cov.: 31 AF XY: 0.0000551 AC XY: 40AN XY: 726334
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with personal and family history of breast cancer and other cancers (Chan 2018); This variant is associated with the following publications: (PMID: 30093976) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in any affected patients. It is classified as VUS in ClinVar (1 star) by GeneDx. It is present in ExAC at 0.07% and gnomAD at 0.1% (19 alleles - too high for gene-disease prevalence). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 31, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at