NM_024675.4(PALB2):c.212-2A>G AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 1, 2024
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:: RCV000160830.13

Allele description [Variation Report for NM_024675.4(PALB2):c.212-2A>G]

NM_024675.4(PALB2):c.212-2A>G

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.212-2A>G

HGVS:

NC_000016.10:g.23636336T>C
NG_007406.1:g.10022A>G
NM_001407296.1:c.152-2A>G
NM_001407297.1:c.212-2A>G
NM_001407298.1:c.212-2A>G
NM_001407299.1:c.212-2A>G
NM_001407300.1:c.212-2A>G
NM_001407301.1:c.212-2A>G
NM_001407302.1:c.212-2A>G
NM_001407304.1:c.-674-2A>G
NM_001407305.1:c.-674-2A>G
NM_001407306.1:c.-674-2A>G
NM_001407307.1:c.-674-2A>G
NM_001407308.1:c.-674-2A>G
NM_001407309.1:c.-674-2A>G
NM_001407310.1:c.-674-2A>G
NM_001407311.1:c.-674-2A>G
NM_001407312.1:c.-105+4774A>G
NM_001407313.1:c.-105+4774A>G
NM_001407314.1:c.48+4774A>G
NM_024675.4:c.212-2A>GMANE SELECT
LRG_308t1:c.212-2A>G
LRG_308:g.10022A>G
NC_000016.9:g.23647657T>C
NM_024675.3:c.212-2A>G

Links:

dbSNP: rs730881879

NCBI 1000 Genomes Browser:

rs730881879

Molecular consequence:

NM_001407312.1:c.-105+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407313.1:c.-105+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407314.1:c.48+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407296.1:c.152-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407297.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407298.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407299.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407300.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407301.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407302.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407304.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407305.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407306.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407307.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407308.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407309.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407310.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407311.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_024675.4:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211503	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV002502673	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26681312, 31589614, 30890586, 25741868
SCV002774369	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 26, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26681312, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211503

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 1, 2024)

germline

clinical testing

Citation Link,

SCV002502673

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 30, 2022)

germline

clinical testing

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

SCV002774369

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Aug 26, 2021)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.

Capalbo A, Valero RA, Jimenez-Almazan J, Pardo PM, Fabiani M, Jiménez D, Simon C, Rodriguez JM.

PLoS Genet. 2019 Oct;15(10):e1008409. doi: 10.1371/journal.pgen.1008409.

PubMed [citation]

PMID:: 31589614
PMCID:: PMC6797235

Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.

Lopez-Perolio I, Leman R, Behar R, Lattimore V, Pearson JF, Castéra L, Martins A, Vaur D, Goardon N, Davy G, Garre P, García-Barberán V, Llovet P, Pérez-Segura P, Díaz-Rubio E, Caldés T, Hruska KS, Hsuan V, Wu S, Pesaran T, Karam R, Vallon-Christersson J, et al.

J Med Genet. 2019 Jul;56(7):453-460. doi: 10.1136/jmedgenet-2018-105834. Epub 2019 Mar 19.

PubMed [citation]

PMID:: 30890586
PMCID:: PMC6591742

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000211503.16

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

Description

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; A different variant at this splice site is reported to cause aberrant splicing leading to skipping of exons 4 and 5, which is predicted to result in a null allele (PMID: 30890586); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 30293905, 32172797, 35626031, 26681312, 30890586)

#	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

From AiLife Diagnostics, AiLife Diagnostics, SCV002502673.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This test has identified one copy of the c.212-2A>G variant in the PALB2 gene. This variant is located in a canonical splice-acceptor site and interferes with normal PALB2 mRNA splicing. The variant has been reported in an individual with breast cancer in the published literature (PMID: 26681312 (2015)). Based on the available information, this variant is classified as pathogenic.

#	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: Oct 8, 2024

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