rs876658534
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM5PP3PP5_Very_Strong
The NM_000077.5(CDKN2A):c.202_203delinsTT(p.Ala68Leu) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A68P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.202_203delinsTT | p.Ala68Leu | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.245_246delinsTT | p.Arg82Leu | missense_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.202_203delinsTT | p.Ala68Leu | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.245_246delinsTT | p.Arg82Leu | missense_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Melanoma-pancreatic cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 08, 2023 | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20340136, 11518711]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9425228, 26775776, 25780468]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2021 | The c.202_203delGCinsTT variant (also known as p.A68L) is located in coding exon 2 of the CDKN2A gene and results from an in-frame deletion of GC and insertion of TT between nucleotide positions 202 and 203. The alanine at codon 68 is replaced by leucine. This alteration has been previously reported in several kindreds with malignant melanoma (Pastorino L et al, Pigment Cell Melanoma Res 2008 Dec; 21(6):700-9; Cust AE et al, J. Med. Genet. 2011 Apr; 48(4):266-72; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Bruno W et al. J Am Acad Dermatol 2016 Feb;74(2):325-32). In one such family, the alteration was found to segregate with disease in four individuals (Soufir N et al, Hum. Mol. Genet. 1998 Feb; 7(2):209-16). In addition, functional studies of A68L mutants have demonstrated decreased binding affinity to CDK4, irregular nuclear localization, and reduced mediation of cell-cycle arrest compared to wild type (Rizos H et al, J. Biol. Chem. 2001 Nov; 276(44):41424-34; McKenzie HA et al. Hum Mutat 2010 Jun;31(6):692-701; Miller PJ et al, Hum. Mutat. 2011 Aug; 32(8):900-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on protein sequence alignment, the amino acid affected by this indel is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial melanoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. This variant disrupts the p.Ala68 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been observed in individuals with CDKN2A (p16INK4a)-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 11518711, 19260062, 20340136, 21462282). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 230375). This variant is also known as c.245_246delinsTT (p.Arg82Leu) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with cutaneous melanoma and/or renal cancer (PMID: 9425228, 18983535, 25780468, 30274933, 30291219, 32782288). It has also been observed to segregate with disease in related individuals. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 68 of the CDKN2A (p16INK4a) protein (p.Ala68Leu). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at