rs2227954
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000075.4(CDK4):c.886C>T(p.His296Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000756 in 1,613,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. H296R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.886C>T | p.His296Tyr | missense_variant | 8/8 | ENST00000257904.11 | |
TSPAN31 | NM_005981.5 | c.*1261G>A | 3_prime_UTR_variant | 6/6 | ENST00000257910.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.886C>T | p.His296Tyr | missense_variant | 8/8 | 1 | NM_000075.4 | P1 | |
TSPAN31 | ENST00000257910.8 | c.*1261G>A | 3_prime_UTR_variant | 6/6 | 1 | NM_005981.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251478Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135916
GnomAD4 exome AF: 0.0000760 AC: 111AN: 1461170Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 49AN XY: 726932
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Familial melanoma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 296 of the CDK4 protein (p.His296Tyr). This variant is present in population databases (rs2227954, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 188345). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Dec 08, 2021 | The CDK4 c.886C>T (p.His296Tyr) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-58142334-G-A?dataset=gnomad_r2_1). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. This variant has been reported in an individual referred for genetic testing likely due to a personal or family history of breast and/or ovarian cancer (PMID: 31159747). To our knowledge, this variant has not been reported in individuals with familial melanoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 11, 2023 | Variant summary: CDK4 c.886C>T (p.His296Tyr) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251478 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05), strongly suggesting that the variant is benign. c.886C>T has been reported in the literature as a VUS in at-least one individual undergoing multigene panel testing for hereditary cancer (example, Tsaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26252490, 31159747). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual referred for hereditary cancer testing (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 26252490, 31159747) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at