NM_024675.4(PALB2):c.2642_2645dup (p.Cys882fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 15, 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:: RCV000160809.11

Allele description [Variation Report for NM_024675.4(PALB2):c.2642_2645dup (p.Cys882fs)]

NM_024675.4(PALB2):c.2642_2645dup (p.Cys882fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.2642_2645dup (p.Cys882fs)

HGVS:

NC_000016.10:g.23626340_23626343dup
NG_007406.1:g.20016_20019dup
NM_024675.4:c.2642_2645dupMANE SELECT
NP_078951.2:p.Cys882fs
NP_078951.2:p.Cys882fs
LRG_308t1:c.2642_2645dup
LRG_308:g.20016_20019dup
LRG_308p1:p.Cys882fs
NC_000016.9:g.23637659_23637660insCAAC
NC_000016.9:g.23637661_23637664dup
NM_024675.3:c.2642_2645dup
NM_024675.3:c.2642_2645dupGTTG
p.C882WfsX3
p.Cys882Trpfs*3

Protein change:

C882fs

Links:

dbSNP: rs730881868

NCBI 1000 Genomes Browser:

rs730881868

Molecular consequence:

NM_024675.4:c.2642_2645dup - 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

Recent activity

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Mus musculus proteolipid protein (myelin) 1 (Plp1), transcript variant 6, mRNA
Mus musculus proteolipid protein (myelin) 1 (Plp1), transcript variant 6, mRNA
gi|1315690765|ref|NM_001359119.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276556	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26681312, 28495237 Citation Link,
SCV001348385	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26681312, 28495237, 31757951, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276556

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 12, 2022)

germline

clinical testing

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

Citation Link,

SCV001348385

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 15, 2022)

germline

clinical testing

PubMed (4)
[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

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

Frey MK, Sandler G, Sobolev R, Kim SH, Chambers R, Bassett RY, Martineau J, Sapra KJ, Boyd L, Curtin JP, Pothuri B, Blank SV.

Gynecol Oncol. 2017 Jul;146(1):123-128. doi: 10.1016/j.ygyno.2017.04.009. Epub 2017 May 8.

PubMed [citation]

PMID:: 28495237

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000276556.7

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

Description

The c.2642_2645dupGTTG pathogenic mutation, located in coding exon 7 of the PALB2 gene, results from a duplication of GTTG between nucleotide positions 2642-2645, causing a translational frameshift with a predicted alternate stop codon (p.C882Wfs*3). This alteration has been identified in patients with breast cancer, who had NGS hereditary cancer panel testing (Frey MK et al. Gynecol. Oncol. 2017 07;146:123-128; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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, SCV001348385.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant inserts 4 nucleotides in exon 7 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. A functional study has reported that this variant results in the loss of PALB2 function in homology-directed repair and resistance to PARP inhibitor assays (PMID: 31757951). This variant has been reported in at least two individuals affected with breast cancer (PMID: 26681312, 28495237). 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: Oct 8, 2024

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