9-21971117-G-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000077.5(CDKN2A):c.242C>G(p.Pro81Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.242C>G | p.Pro81Arg | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.285C>G | p.Thr95= | synonymous_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.242C>G | p.Pro81Arg | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.285C>G | p.Thr95= | synonymous_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2021 | The p.P81R pathogenic mutation (also known as c.242C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 242. The proline at codon 81 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple cohorts of high-risk melanoma patients who either had multiple primary malignant melanomas and/or a family history of malignant melanoma as well as a pancreatic cancer patient (Helsing P et al. Genes Chromosomes Cancer, 2008 Feb;47:175-84; Müller C et al. Br. J. Dermatol., 2016 Jun;174:1308-17; Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Mantripragada KC et al. J Oncol Pract, 2016 Apr;12:e396-404). This alteration segregates with melanoma and pancreatic cancer in multiple individuals from multiple families (Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Ambry internal data). Based on internal structural analysis, this alteration lies within a mutational hotspot and will destabilize local structure of the binding interface leading to significantly impaired binding to CDK4 and CDK6 (Ambry internal data; Russo AA et al. Nature, 1998 Sep;395:237-43). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 07, 2021 | This missense variant replaces proline with arginine at codon 81 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. Other variants at this codon have been observed to be defective for CDK4 binding (PMID: 10389768, 20340136). This variant has been reported in individuals affected with melanoma and pancreatic cancer (PMID: 18023021, 26800492, 26907448, 27804060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial melanoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2021 | This sequence change replaces proline with arginine at codon 81 of the CDKN2A (p16INK4a) protein (p.Pro81Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with melanoma and multiple primary melanoma (PMID: 18023021, 21462282, 26800492, 19260062, 27804060). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at