NM_002734.5(PRKAR1A):c.761_762del (p.Ser254fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 19, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003298031.3

Allele description [Variation Report for NM_002734.5(PRKAR1A):c.761_762del (p.Ser254fs)]

NM_002734.5(PRKAR1A):c.761_762del (p.Ser254fs)

Gene:

PRKAR1A:protein kinase cAMP-dependent type I regulatory subunit alpha [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17q24.2

Genomic location:

Preferred name:

NM_002734.5(PRKAR1A):c.761_762del (p.Ser254fs)

HGVS:

NC_000017.11:g.68527890CT[1]
NG_007093.3:g.119268CT[1]
NM_001276289.2:c.761_762del
NM_001276290.1:c.761_762del
NM_001278433.2:c.761_762del
NM_001369389.1:c.761_762del
NM_001369390.1:c.761_762del
NM_002734.3:c.761_762delCT
NM_002734.5:c.761_762delMANE SELECT
NM_212471.3:c.761_762del
NM_212472.2:c.761_762del
NP_001263218.1:p.Ser254fs
NP_001263219.1:p.Ser254fs
NP_001265362.1:p.Ser254fs
NP_001356318.1:p.Ser254fs
NP_001356319.1:p.Ser254fs
NP_002725.1:p.Ser254fs
NP_997636.1:p.Ser254fs
NP_997637.1:p.Ser254fs
LRG_514t1:c.761_762del
LRG_514t2:c.761_762del
LRG_514:g.119268CT[1]
LRG_514p2:p.Ser254fs
NC_000017.10:g.66524031CT[1]
NM_002734.4:c.761_762del

Protein change:

S254fs

Links:

OMIM: 188830.0006

Molecular consequence:

NM_001276289.2:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001276290.1:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001278433.2:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369389.1:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369390.1:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002734.5:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_212471.3:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_212472.2:c.761_762del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004000410	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 19, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004000410

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 19, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV004000410.3

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

Description

The c.761_762delCT pathogenic mutation, located in coding exon 7 of the PRKAR1A gene, results from a deletion of two nucleotides at nucleotide positions 761 to 762, causing a translational frameshift with a predicted alternate stop codon (p.S254Yfs*15). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PRKAR1A-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Loss-of-function variants subject to nonsense mediated decay (NMD) in PRKAR1A are known to cause Carney complex; however, such associations with acrodysostosis have not been reported (Michot. et al. Eur J Hum Genet 26, 1611–1622 (2018); Bertherat J et al. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91; Jafari N et al. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2024716118). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is pathogenic for Carney complex; however, the association of this alteration with acrodysostosis is unlikely.

#	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

Last Updated: Sep 16, 2024

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