NM_000321.3(RB1):c.264+5G>A AND Retinoblastoma

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 15, 2021
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:: RCV001301388.9

Allele description [Variation Report for NM_000321.3(RB1):c.264+5G>A]

NM_000321.3(RB1):c.264+5G>A

Gene:

RB1:RB transcriptional corepressor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.2

Genomic location:

Preferred name:

NM_000321.3(RB1):c.264+5G>A

HGVS:

NC_000013.11:g.48307411G>A
NG_009009.1:g.8665G>A
NM_000321.3:c.264+5G>AMANE SELECT
LRG_517t1:c.264+5G>A
LRG_517:g.8665G>A
NC_000013.10:g.48881547G>A
NM_000321.2:c.264+5G>A

Links:

dbSNP: rs1131690853

NCBI 1000 Genomes Browser:

rs1131690853

Molecular consequence:

NM_000321.3:c.264+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Retinoblastoma (RB1)
Synonyms:: Eye cancer, retinoblastoma; RETINOBLASTOMA, SOMATIC
Identifiers:: MONDO: MONDO:0008380; MeSH: D012175; MedGen: C0035335; Orphanet: 790; OMIM: 180200; Human Phenotype Ontology: HP:0009919

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001490555	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 31568710, 33225895, 28492532
SCV002032313	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely pathogenic (Dec 9, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001490555

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 15, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002032313

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

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Likely pathogenic
(Dec 9, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001490555.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1004646). This variant has been observed in individuals with retinoblastoma (PMID: 31568710, 33225895; Invitae; External communication). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein. It affects a nucleotide within the consensus splice site.

#	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 St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002032313.2

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

Description

The RB1 c.264+5G>A intronic change results in a G to A substitution at the +5 position of intron 2 of RB1 gene. This variant is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may abolish the native splice donor site and likely result in an absent or disrupted protein product (PP3). Reverse-transcriptase PCR analysis identified skipping of exon 2 (PS3_supporting, outside lab testing). This variant has been reported in four individuals with retinoblastoma (PS4; PMID: 33225895, 31568710, internal data, personal communication). In addition, this variant was identified as de novo in an individual with unilateral retinoblastoma (PS2_supporting; PMID: 33225895). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied: PS4, PS3_supporting, PS2_supporting, PM2_supporting, PP3.

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

Last Updated: Feb 20, 2024

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