9-21974682-A-G

Variant names:

• chr9-21974682-A-G
• rs199907548
• NM_000077.5:c.146T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1 PM5 PP5 BP4 BS1_Supporting BS2

The NM_000077.5(CDKN2A):​c.146T>C​(p.Ile49Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. I49M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:10 O:1
• Conservation: PhyloP100: 5.56
• Publications: 38 publications found

Genes affected

CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

CDKN2A Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 uncertain in NM_000077.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21974682-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 9-21974682-A-G is Pathogenic according to our data. Variant chr9-21974682-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127523.
• BP4: Computational evidence support a benign effect (MetaRNN=0.063048065). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000723 (11/152212) while in subpopulation AMR AF = 0.000654 (10/15292). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.146T>C	p.Ile49Thr	missense	Exon 1 of 3	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3474T>C		intron	N/A	NP_478102.2
	CDKN2A	NM_001195132.2		c.146T>C	p.Ile49Thr	missense	Exon 1 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.146T>C	p.Ile49Thr	missense	Exon 1 of 3	ENSP00000307101.5
	CDKN2A	ENST00000498124.1	TSL:1	c.146T>C	p.Ile49Thr	missense	Exon 1 of 4	ENSP00000418915.1
	CDKN2A	ENST00000380151.3	TSL:1	n.146T>C		non_coding_transcript_exon	Exon 1 of 3	ENSP00000369496.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000625 AC: 156 AN: 249454 AF XY: 0.000489

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.000102 AC XY: 74 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00369 AC: 165 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.000654 AC: 10 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000120 Hom.: 1

Bravo AF: 0.000298

ExAC AF: 0.000436 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2 Uncertain:2

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces isoleucine with threonine at codon 49 of the CDKN2A (p16INK4A) protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported the mutant protein to be partially to fully functional in CDK4 and CDK6 binding in yeast and mammalian assays (PMID: 7566978, 7647780, 8573142, 10389768, 10719365, 21462282). Cell cycle and growth arrest assays have produced inconsistent results with the mutant protein showing normal activity (PMID: 33823155) or significantly reduced activity (PMID: 10389768, 21462282, 35001868). This variant has been reported in multiple individuals and families affected with melanoma (PMID: 7987387, 11687599, 15075790, 16234564, 16896043, 17218939, 18335566, 21085193, 21462282, 26681309). This variant has also been identified in 158/280824 chromosomes (157/35432 Latino chromosomes) by the Genome Aggregation Database (gnomAD). Although this variant has been observed in multiple individuals affected with melanoma, it occurs at a high allele frequency in the general population (0.44% in the Latino population). 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.

Jan 24, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 12, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I49T variant (also known as c.146T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 146. The isoleucine at codon 49 is replaced by threonine, an amino acid with similar properties. This variant has been seen in multiple individuals with personal and/or family histories of pancreatic cancer (Ambry internal data). Case-control analysis determined this variant results in increased risk for melanoma and pancreatic cancer (Ambry internal data). This variant has been reported in patients with no family history of melanoma but who had a single primary melanoma or multiple primary melanomas (Berwick M et al. Eur. J. Cancer Prev. 2004 Feb;13:65-70; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15). It has also been reported in multiple familial melanoma cases, however, in one case, it did not completely segregate with disease (Hussussian CJ et al. Nat. Genet. 1994 Sep;8:15-21; Puig S et al. Genet. Med. 2016 Jul;18:727-36). Multiple functional studies have demonstrated that this variant diminishes the binding activity of p16 to CDK4 and CDK6 and displays reduced ability to affect Rb dephosphorylation, however the degree of effect is shown to be more intermediate than other known pathogenic variants (Ranade K et al. Nat. Genet. 1995 May;10:114-6; Reymond A et al. Oncogene. 1995 Sep;11:1173-8; Yang R et al. Biochem. Biophys. Res. Commun. 1996 Jan;218:254-9; Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305-12). Cell cycle inhibition assays have demonstrated that this variant is functionally deleterious (Miller, PJ et al. Hum Mutat 2011 Aug;32(8):900-11; Kimura H et al. Elife 2022 Jan;11:). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Mar 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKN2A c.146T>C (p.Ile49Thr) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. At-least one additional variant at this codon (c.146T>G, p.Ile49Ser) has been observed with a pathogenic outcome, supporting a critical relevance of this residue to CDKN2A protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 249454 control chromosomes, predominantly at a frequency of 0.0045 within the Latino subpopulation in the gnomAD database. The observed variant frequency is higher than expected for a pathogenic variant. c.146T>C has been reported in the literature in multiple individuals affected with melanoma and/or pancreatic cancer with some reports of non-segregation and/or variable penetrance (e.g. Hussussian_1994, Begg_2005, Capanu_2008, Miller_2011, Puig_2016, internal testing data). In addition, this variant was also found in patients with HBOC, CRC, or LS (e.g. Yurgelun_2015, Ricker_2017, Slavin_2018, Oliver_2019). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TP53 c.818G>A, p.Arg273His) however, this is not considered as a supportive evidence towards non-causation in the context of this evaluation. Multiple experimental studies showed conflicting results including: decreased inhibition of cyclinD1/CDK4 and cyclin D1/CDK6 activity (Ranade_1995), decreased binding activity to CDK4 (Yang_1996, Reymond_1995), no effect on binding to the kinases but substantially diminished ability to inhibit cell growth and mis-localization (Walker_1999), loss of function in a cell cycle arrest assay (Miller_2011) and most recently, cell cycle suppression that was similar to WT (Horn_2021). The following publications have been ascertained in the context of this evaluation (PMID: 16234564, 27756164, 18335566, 27960642, 28765326, 33823155, 7987387, 9166859, 21462282, 16818274, 18519632, 31921681, 26681309, 7647780, 7566978, 28640387, 7718873, 30339520, 10389768, 8573142, 25980754). ClinVar contains an entry for this variant (Variation ID: 127523). Based on the evidence outlined above, the variant was classified as likely pathogenic.

CDKN2A-related disorder Pathogenic:2

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDKN2A c.146T>C variant is predicted to result in the amino acid substitution p.Ile49Thr. This variant is also in the coding region of an alternate transcript, NM_058197:c.146T>C (p.Ile49Thr). This variant has been reported in multiple individuals with or without family history of melanoma; in one of these cases the variant did not segregate with the disease in the family (examples, Hussussian et al. 1994. PubMed ID: 7987387; Table S3, Taylor et al. 2017. PubMed ID: 28830827; Table 3, Puig et al 2015. PubMed ID: 26681309). This variant has also been observed in our laboratory in a patient with cancer who has a pathogenic BRCA1 variant (internal database). Functional studies have suggested that this variant may mildly impact enzyme function (Ranade et al. 1995. PubMed ID: 7647780; Walker et al. 1999. PubMed ID: 10389768). This variant has been reported in approximately 0.44% of individuals of Latino background in a large population database. This variant is interpreted as a variant of uncertain significance or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127523/). In summary, this variant is interpreted as likely pathogenic with possibly reduced penetrance.

Mar 19, 2025

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Melanoma-pancreatic cancer syndrome Pathogenic:1 Uncertain:1

Jul 12, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 12, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868, 10389768, 21462282]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21462282, 17218939, 30207590, Myriad internal data].

not specified Uncertain:2

Dec 19, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.146T>C; p.Ile49Thr variant (rs199907548) is reported in the literature in individuals affected with melanoma or breast cancer (Hussussian 1994, Kurian 2014, Orlow 2007, Puig 2016, Taylor 2017). However, in one family this variant did not segregate with disease (Hussussian 1994), while melanoma was not reported in nine first-degree relatives of another carrier (Orlow 2007). This variant is found in the Latino population with an overall allele frequency of 0.44% (157/35432 alleles) in the Genome Aggregation Database. The isoleucine at codon 49 is moderately conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and another variant at this codon (p.Ile49Ser) has been reported in melanoma patients and is considered pathogenic (Orlow 2007, Taylor 2017). Functional analyses indicate that the p.Ile49Thr variant fails to arrest growth of melanoma or osteosarcoma cells like wildtype protein (Miller 2011, Walker 1999), and it exhibits roughly half of wildtype activity in an in vitro assay for inhibition of cyclin D1-CDK signaling (Ranade 1995). However, due to conflicting information, the clinical significance of the p.Ile49Thr variant is uncertain at this time. References: Hussussian CJ et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994 Sep;8(1):15-21. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. Miller PJ et al. Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat. 2011 Aug;32(8):900-11. Orlow I et al. CDKN2A germline mutations in individuals with cutaneous malignant melanoma. J Invest Dermatol. 2007 May;127(5):1234-43. Puig S et al. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. Genet Med. 2016 Jul;18(7):727-36. Ranade K et al. Mutations associated with familial melanoma impair p16INK4 function. Nat Genet. 1995 May;10(1):114-6. Taylor NJ et al. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. J Invest Dermatol. 2017 Dec;137(12):2606-2612. Walker GJ et al. Functional reassessment of P16 variants using a transfection-based assay. Int J Cancer. 1999 Jul 19;82(2):305-12.

Nov 15, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the CDKN2A gene demonstrated a sequence change, c.146T>C, in exon 1 that results in an amino acid change, p.Ile49Thr. This sequence change has been described in the gnomAD database with a frequency of 0.44% in the Latino subpopulation (dbSNP rs199907548). The p.Ile49Thr change affects a highly conserved amino acid residue located in a domain of the CDKN2A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile49Thr substitution. This sequence change has been reported in individuals with melanoma (PMID: 7987287, 17218939, 26681309). Experimental studies provide conflicting evidence on the effect of this sequence change on protein function (PMID: 8573142, 10389768, 21462282). Due to insufficient evidences, the clinical significance of the p.Ile49Thr change remains unknown at this time.

not provided Uncertain:2

May 16, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant has been reported in individuals with sporadic and familial melanoma and/or pancreatic cancer, and segregated with pancreatic cancer in at least one family (PMID: 7987387, 15075790, 24733792, 26670561, 25186627, 26681309, 30207590, GeneDx, External communication with outside laboratories); Published functional studies are conflicting regarding the effect on binding to CDK4 and ability to inhibit cell growth (PMID: 7647780, 7566978, 10389768, 10719365, 21462282, 33823155, 35001868); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11687599, 15075790, 7647780, 10389768, 21680795, 11518711, 9823374, 24733792, 26670561, 26667234, 28454591, 10719365, 8573142, 28231819, 21085193, 29415044, 30207590, 25980754, 16896043, 26681309, 16234564, 17218939, 25186627, 7566978, 21462282, 28830827, 31921681, 32191290, 7987387, 35366121, 38093606, 35001868, 33823155, 9529249, 9653180, 16173922)

Jun 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.146T>C (p.Ile49Thr) variant has been reported in the published literature in individuals with melanoma (PMIDs: 26681309 (2016), 17218939 (2007), 16234564 (2005), 15075790 (2004), 7987387 (1994)), hereditary breast and/or ovarian cancer (PMIDs: 31921681 (2019), 30339520 (2018), 24733792 (2014)), and unspecified cancers (PMID: 30339520 (2018)). Some functional studies suggest this variant may impair CDKN2A binding and cell cycle arrest function (PMIDs: 7566978 (1995), 10389768 (1999), 10719365 (2000), and 21462282 (2011)), while other studies conflict with this data (PMID: 33823155 (2020)). The frequency of this variant in the general population, 0.0044 (157/35432 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Pathogenic:1

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial melanoma Pathogenic:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 49 of the CDKN2A (p16INK4a) protein (p.Ile49Thr). This variant is present in population databases (rs199907548, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 7987387, 16896043, 21462282, 26681309; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as c.140T>C (p.Ile41Thr). ClinVar contains an entry for this variant (Variation ID: 127523). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 7566978, 7647780, 8573142, 10389768, 10719365, 21462282). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Melanoma and neural system tumor syndrome Uncertain:1

Mar 28, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Acute lymphoid leukemia Uncertain:1

Sep 23, 2023

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteoblastic osteosarcoma Uncertain:1

Apr 03, 2017

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Melanoma and neural system tumor syndrome;C1838547:Melanoma-pancreatic cancer syndrome Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 05-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.063	T
MetaSVM	Uncertain	0.0011	D
PhyloP100		5.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.99
MPC		1.4
ClinPred		0.25	T
GERP RS		4.9
PromoterAI		-0.033	Neutral
Varity_R		0.49
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199907548; hg19: chr9-21974681; COSMIC: COSV58687879;