rs587778637

chr13-48303971-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000321.3(RB1):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,503,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P20S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 1.47

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 13-48303971-C-T is Benign according to our data. Variant chr13-48303971-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135115.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=4}.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.59C>T	p.Pro20Leu	missense_variant	1/27	ENST00000267163.6
RB1	NM_001407165.1	c.59C>T	p.Pro20Leu	missense_variant	1/27
RB1	NM_001407166.1	c.59C>T	p.Pro20Leu	missense_variant	1/17
RB1	NM_001407167.1	c.59C>T	p.Pro20Leu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.59C>T	p.Pro20Leu	missense_variant	1/27	1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000250

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000128 AC: 13 AN: 101296 Hom.: 0 AF XY: 0.000123 AC XY: 7 AN XY: 56758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000973

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000146 AC: 198 AN: 1351810 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 93 AN XY: 666756

Gnomad4 AFR exome AF: 0.000109

Gnomad4 AMR exome AF: 0.0000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000285

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74234

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinoblastoma Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces proline with leucine at codon 20 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with retinoblastoma (PMID: 12541220, 14722923, 16343894, 29261756), but also in unaffected individuals (PMID: 16343894, 24728327, 29261756). This variant has been identified in 16/132530 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2022	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. -

RB1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2023

The RB1 c.59C>T variant is predicted to result in the amino acid substitution p.Pro20Leu. This variant was reported in an individual with retinoblastoma (Parma et al. 2017. PubMed ID: 29261756, described as g.2118C>T), but was also found in the patient's asymptomatic mother and has been reported in a healthy ancestrally diverse cohort (Bodian et al. 2014. PubMed ID: 24728327, supplementary data). This variant was also described as a variant of uncertain significance in cohort of individuals with breast cancer (Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/135115/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	21
Dann	Benign	0.87
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	0.062
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.90	N;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.014	D;.;.
Sift4G	Uncertain	0.037	D;.;.
Polyphen		0.99	D;.;.
Vest4		0.21
MVP		0.96
MPC		0.45
ClinPred		0.18	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.12
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778637; hg19: chr13-48878107; COSMIC: COSV105859610; COSMIC: COSV105859610;