Submissions for variant NM_004064.5(CDKN1B):c.482C>G (p.Ser161Cys)

gnomAD frequency: 0.00014  dbSNP: rs373917399

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227030	SCV000288087	uncertain significance	Multiple endocrine neoplasia type 4	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the CDKN1B protein (p.Ser161Cys). This variant is present in population databases (rs373917399, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia (PMID: 35355569). ClinVar contains an entry for this variant (Variation ID: 239625). 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.
Illumina Laboratory Services, Illumina	RCV000227030	SCV000377024	benign	Multiple endocrine neoplasia type 4	2018-01-12	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	RCV000422614	SCV000529831	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic neuroendocrine tumor (Lavezzi et al., 2022); This variant is associated with the following publications: (PMID: 35355569, 36520683)
Ambry Genetics	RCV001023120	SCV001184947	likely benign	Hereditary cancer-predisposing syndrome	2020-03-27	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.
Sema4, Sema4	RCV001023120	SCV002527680	likely benign	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000422614	SCV002545010	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	CDKN1B: BP4, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321562	SCV004027265	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417816	SCV004116481	uncertain significance	CDKN1B-related disorder	2023-02-08	criteria provided, single submitter	clinical testing	The CDKN1B c.482C>G variant is predicted to result in the amino acid substitution p.Ser161Cys. This variant has been reported in an individual with multiple endocrine neoplasia (Lavezzi et al. 2022. PubMed ID: 35355569). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD, including one homozygous observation (http://gnomad.broadinstitute.org/variant/12-12871765-C-G). It has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/239625/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000422614	SCV004220760	likely benign	not provided	2023-01-16	criteria provided, single submitter	clinical testing