NM_024675.4(PALB2):c.3026_3027insA (p.Pro1009_Glu1010insTer) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 25, 2022
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:: RCV002435932.3

Allele description [Variation Report for NM_024675.4(PALB2):c.3026_3027insA (p.Pro1009_Glu1010insTer)]

NM_024675.4(PALB2):c.3026_3027insA (p.Pro1009_Glu1010insTer)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3026_3027insA (p.Pro1009_Glu1010insTer)

HGVS:

NC_000016.10:g.23621448_23621449insT
NG_007406.1:g.24909_24910insA
NM_001407296.1:c.2966_2967insA
NM_001407297.1:c.2954_2955insA
NM_001407298.1:c.2864_2865insA
NM_001407299.1:c.3026_3027insA
NM_001407301.1:c.3026_3027insA
NM_001407302.1:c.2864_2865insA
NM_001407304.1:c.2141_2142insA
NM_001407305.1:c.2141_2142insA
NM_001407306.1:c.2141_2142insA
NM_001407307.1:c.1979_1980insA
NM_001407308.1:c.2141_2142insA
NM_001407309.1:c.2141_2142insA
NM_001407310.1:c.2141_2142insA
NM_001407311.1:c.2141_2142insA
NM_001407312.1:c.1238_1239insA
NM_001407313.1:c.1238_1239insA
NM_001407314.1:c.560_561insA
NM_024675.4:c.3026_3027insAMANE SELECT
NP_001394225.1:p.Glu990Terfs
NP_001394226.1:p.Glu986Terfs
NP_001394227.1:p.Glu956Terfs
NP_001394228.1:p.Glu1010Terfs
NP_001394230.1:p.Glu1010Terfs
NP_001394231.1:p.Glu956Terfs
NP_001394233.1:p.Glu715Terfs
NP_001394234.1:p.Glu715Terfs
NP_001394235.1:p.Glu715Terfs
NP_001394236.1:p.Glu661Terfs
NP_001394237.1:p.Glu715Terfs
NP_001394238.1:p.Glu715Terfs
NP_001394239.1:p.Glu715Terfs
NP_001394240.1:p.Glu715Terfs
NP_001394241.1:p.Glu414Terfs
NP_001394242.1:p.Glu414Terfs
NP_001394243.1:p.Glu188Terfs
NP_078951.2:p.Glu1010Terfs
NP_078951.2:p.Pro1009_Glu1010insTer
LRG_308t1:c.3026_3027insA
LRG_308:g.24909_24910insA
LRG_308p1:p.Glu1010Terfs
NC_000016.9:g.23632769_23632770insT
NM_024675.3:c.3026_3027insA

Molecular consequence:

NM_001407296.1:c.2966_2967insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407297.1:c.2954_2955insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407298.1:c.2864_2865insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407299.1:c.3026_3027insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407301.1:c.3026_3027insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407302.1:c.2864_2865insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407304.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407305.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407306.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407307.1:c.1979_1980insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407308.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407309.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407310.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407311.1:c.2141_2142insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407312.1:c.1238_1239insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407313.1:c.1238_1239insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407314.1:c.560_561insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024675.4:c.3026_3027insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407296.1:c.2966_2967insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407297.1:c.2954_2955insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407298.1:c.2864_2865insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407299.1:c.3026_3027insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407301.1:c.3026_3027insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407302.1:c.2864_2865insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407304.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407305.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407306.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407307.1:c.1979_1980insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407308.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407309.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407310.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407311.1:c.2141_2142insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407312.1:c.1238_1239insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407313.1:c.1238_1239insA - nonsense - [Sequence Ontology: SO:0001587]
NM_001407314.1:c.560_561insA - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002753412	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 25, 2022)	germline	clinical testing	Citation Link,
SCV004357824	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34359559, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002753412

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 25, 2022)

germline

clinical testing

Citation Link,

SCV004357824

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 25, 2022)

germline

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

Citations

PubMed

TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing.

Lesueur F, Eon-Marchais S, Bonnet-Boissinot S, Beauvallet J, Dondon MG, Golmard L, Rouleau E, Garrec C, Martinez M, Toulas C, Nguyen TD, Brayotel F, Crivelli L, Maugard CM, Bubien V, Sevenet N, Gesta P, Chieze-Valero S, Nambot S, Goussot V, Mari V, Popovici C, et al.

Cancers (Basel). 2021 Jul 21;13(15). doi:pii: 3659. 10.3390/cancers13153659.

PubMed [citation]

PMID:: 34359559
PMCID:: PMC8345200

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV002753412.2

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

Description

The c.3026_3027insA pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from an insertion of one nucleotide at position 3026, causing a translational frameshift with a predicted alternate stop codon (p.E1010*). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004357824.1

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

Description

This variant inserts 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a suspected hereditary breast and ovarian cancer family (PMID: 34359559). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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 8, 2024

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