Submissions for variant NM_024529.5(CDC73):c.1304T>C (p.Met435Thr)

gnomAD frequency: 0.00003  dbSNP: rs202209013

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473561	SCV000541305	uncertain significance	Parathyroid carcinoma	2024-01-05	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002381287	SCV002691320	likely benign	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002482952	SCV002790655	uncertain significance	Hyperparathyroidism 1; Parathyroid carcinoma; Hyperparathyroidism 2 with jaw tumors	2022-01-02	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153326	SCV003843390	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460547	SCV004215573	uncertain significance	Hyperparathyroidism 1	2023-09-28	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034781	SCV000043242	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.