Submissions for variant NM_000077.5(CDKN2A):c.341C>T (p.Pro114Leu)

dbSNP: rs121913386

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569438	SCV000669192	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-19	criteria provided, single submitter	clinical testing	The p.P114L variant (also known as c.341C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 341. The proline at codon 114 is replaced by leucine, an amino acid with similar properties. This alteration is non functional in multiple studies including with respect to CDK4/6 binding and cell cycle control (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Parry and Peters, Mol. Cell. Biol. 1996 Jul;16(7):3844-52; Tevelev A et al. Biochemistry 1996 Jul;35(29):9475-87). This alteration has been observed in multiple individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data; Fargnoli MC et al. J. Invest. Dermatol., 1998 Dec;111:1202-6; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795116	SCV000934558	uncertain significance	Familial melanoma	2020-02-11	criteria provided, single submitter	clinical testing	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. This variant has been reported to affect CDKN2A (p16INK4a) protein function (PMID: 7777060, 7777061, 8668202, 9328469, 9053859, 12606942, 21462282). This variant has been observed in several individuals affected with melanoma (PMID: 9856841, 21462282). Segregation studies have not been reported. ClinVar contains an entry for this variant (Variation ID: 77637). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 114 of the CDKN2A (p16INK4a) protein (p.Pro114Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000795116	SCV001478773	likely pathogenic	Familial melanoma	2021-01-08	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.341C>T (p.Pro114Leu) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239394 control chromosomes (gnomAD). c.341C>T has been reported as a germline mutation in the literature in several individuals affected with familial melanoma (e.g. Fargnoli_1998, Spica_2011, Pellegrini_2019). However, no co-segregation studies have been performed, therefore these data do not allow any definitive conclusion about variant significance. The variant has also been reported numerous times as a somatic mutation in melanomas and other cancers. Multiple publications report experimental evidence evaluating an impact on protein function, indicating that the variant is non-functional and unable to bind Cdk4/Cdk6 or induce G1 cell cycle arrest in-vitro (e.g. Koh_1995, Parry_1996, Byeon_1998, Jiang_1998, Gump_2001, Miller _2011). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Database of Curated Mutations (DoCM)	RCV000424989	SCV000505627	likely pathogenic	Melanoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442671	SCV000505898	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425751	SCV000505899	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435136	SCV000505900	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444494	SCV000505901	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332113	SCV004040565	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research