Submissions for variant NM_024529.5(CDC73):c.1032T>G (p.Val344=)

gnomAD frequency: 0.00070  dbSNP: rs148612206

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234138	SCV000290762	benign	Parathyroid carcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315634	SCV000352137	likely benign	Hyperparathyroidism 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000234138	SCV000352138	benign	Parathyroid carcinoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000261802	SCV000352139	benign	Hyperparathyroidism 2 with jaw tumors	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000441371	SCV000512502	likely benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001009738	SCV001169841	likely benign	Hereditary cancer-predisposing syndrome	2018-11-30	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.
CeGaT Center for Human Genetics Tuebingen	RCV000441371	SCV004125132	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CDC73: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488491	SCV004241302	benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: CDC73 c.1032T>G (p.Val344Val) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 211726 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 286 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDC73 causing Hyperparathyroidism-Jaw Tumor Syndrome phenotype (4.1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1032T>G in individuals affected with Hyperparathyroidism-Jaw Tumor Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.