NM_000075.4(CDK4):c.625C>T (p.Arg209Cys) AND Melanoma, cutaneous malignant, susceptibility to, 3

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000409800.14

Allele description [Variation Report for NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)]

NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)

Gene:

CDK4:cyclin dependent kinase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q14.1

Genomic location:

Preferred name:

NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)

Other names:

p.R209C:CGT>TGT

HGVS:

NC_000012.12:g.57750663G>A
NG_007484.2:g.6719C>T
NM_000075.4:c.625C>TMANE SELECT
NP_000066.1:p.Arg209Cys
LRG_490t1:c.625C>T
LRG_490:g.6719C>T
NC_000012.11:g.58144446G>A
NM_000075.2:c.625C>T
NM_000075.3:c.625C>T
p.R209C

Protein change:

R209C

Links:

dbSNP: rs140644696

NCBI 1000 Genomes Browser:

rs140644696

Molecular consequence:

NM_000075.4:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Melanoma, cutaneous malignant, susceptibility to, 3
Synonyms:: Cutaneous malignant melanoma 3
Identifiers:: MONDO: MONDO:0012183; MedGen: C1836892; Orphanet: 618; OMIM: 609048

Recent activity

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autoinducer-2 (AI-2) modifying protein LsrG [Shigella flexneri 2a str. 301]
autoinducer-2 (AI-2) modifying protein LsrG [Shigella flexneri 2a str. 301]
gi|24112948|ref|NP_707458.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488928	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jul 19, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26252490, 26580448, 25186627, 26534844 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000891027	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Aug 30, 2023)	germline	clinical testing	Citation Link,
SCV004020048	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 7, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000488928

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Jul 19, 2016)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV000891027

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

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Aug 30, 2023)

germline

clinical testing

Citation Link,

SCV004020048

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Uncertain significance
(Mar 7, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies.

N N, Zhu H, Liu J, V K, C GP, Chakraborty C, Chen L.

PLoS One. 2015;10(8):e0133969. doi: 10.1371/journal.pone.0133969.

PubMed [citation]

PMID:: 26252490
PMCID:: PMC4529227

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000488928.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV000891027.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CDK4 c.625C>T (p.Arg209Cys) missense change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with pancreatic cancer (PMID: 28726808) and breast cancer (PMID: 25186627, 26534844). To our knowledge, this variant has not been reported in individuals with familial melanoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004020048.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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