ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.457G>T (p.Asp153Tyr) (rs45476696)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223581 SCV000274983 pathogenic Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Last nucleotide of exon,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000223581 SCV000684534 pathogenic Hereditary cancer-predisposing syndrome 2016-09-30 criteria provided, single submitter clinical testing
Counsyl RCV000576665 SCV000677826 likely pathogenic Melanoma-pancreatic cancer syndrome 2017-02-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000223581 SCV000695347 pathogenic Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The CDKN2A c.457G>T (p.Asp153Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant leads to substitution of the last nucleotide in exon 2 and 5/5 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 118670 control chromosomes from ExAC. This germline variant has been found in familial cases with cutaneous malignant melanoma and pancreatic cancer, including evidence of cosegregation with disease ((Lynch_2002, Loo_2003, Rutter_2003, McWilliams_2011, Lucas_2014). Functional studies have shown that this variant causes aberrant splicing in a similar manner with another splice-site variant c.457+1G>T. This variant leads to activation of a cryptic donor site located within exon 2, thus splicing out 74 bp encoded by exon 2. The predicted protein product of the mutant lacks 24 amino acids encoded by exon 2 and possesses a frameshift in exon 3 that yields six amino acids followed by a termination codon (Loo_2003, Rutter_2003). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000198192 SCV000253763 pathogenic Hereditary cutaneous melanoma 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 153 of the CDKN2A (p16INK4a) protein (p.Asp153Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with CDKN2A (p16INK4a)-related diseases in multiple families (PMID: 14508519, Invitae). It has also been reported in many other individuals affected with melanoma and pancreatic carcinoma (PMID: 12853981, 10627132, 16905682, 20539244, 20876876, 21150883, 25356972). ClinVar contains an entry for this variant (Variation ID: 216035). Experimental studies have shown that this variant disrupts splicing of the p16INK4a transcript. RT-PCR studies have shown that this variant causes the activation of a cryptic splice donor site within exon 2, and is expected to result in the replacement of the final 27 amino acid residues of p16INK4a with 6 alternative amino acid residues (PMID: 12853981, 14508519). For these reasons, this variant has been classified as Pathogenic.

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