rs202209013
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_024529.5(CDC73):āc.1304T>Cā(p.Met435Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,612,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. M435V) has been classified as Uncertain significance.
Frequency
Consequence
NM_024529.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDC73 | NM_024529.5 | c.1304T>C | p.Met435Thr | missense_variant | 14/17 | ENST00000367435.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC73 | ENST00000367435.5 | c.1304T>C | p.Met435Thr | missense_variant | 14/17 | 1 | NM_024529.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251296Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135796
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1460004Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 726490
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Quezada Urban et al., 2018); This variant is associated with the following publications: (PMID: 15923622, 30262796, 22703879) - |
Parathyroid carcinoma;C1704981:Hyperparathyroidism 2 with jaw tumors;C1840402:Hyperparathyroidism 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 02, 2022 | - - |
Hyperparathyroidism 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2023 | - - |
Parathyroid carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 435 of the CDC73 protein (p.Met435Thr). This variant is present in population databases (rs202209013, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer susceptibility (PMID: 30262796). ClinVar contains an entry for this variant (Variation ID: 41848). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDC73 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. - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at