NM_024675.4(PALB2):c.172_175del (p.Gln60fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 21, 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:: RCV000116073.22

Allele description [Variation Report for NM_024675.4(PALB2):c.172_175del (p.Gln60fs)]

NM_024675.4(PALB2):c.172_175del (p.Gln60fs)

Genes:

DCTN5:dynactin subunit 5 [Gene - OMIM - HGNC]
PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.172_175del (p.Gln60fs)

HGVS:

NC_000016.10:g.23637886ACAA[1]
NC_000016.9:g.23649207_23649210del
NG_007406.1:g.8465TTGT[1]
NM_024675.4:c.172_175delMANE SELECT
NP_078951.2:p.Gln60fs
LRG_308:g.8465TTGT[1]
NC_000016.9:g.23649207ACAA[1]
NC_000016.9:g.23649207_23649210del
NC_000016.9:g.23649211_23649214del
NM_024675.3:c.172_175delTTGT
NM_024675.4:c.172_175del
NM_024675.4:c.172_175delTTGTMANE SELECT
p.Gln60Argfs*7
p.Gln60ArgfsX7
p.Q60Rfs*7
p.Q60RfsX7

Protein change:

Q60fs

Links:

OMIM: 610355.0007; dbSNP: rs180177143

NCBI 1000 Genomes Browser:

rs180177143

Molecular consequence:

NM_024675.4:c.172_175del - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172718	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19264984, 21285249, 22310028, 24136930, 25959805, 28279176, 29052111, 29753700 Citation Link,
SCV000685897	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2022)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 19264984, 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 25959805, 26283626, 27038244, 27616075, 28724667, 29052111, 29753700, 33471991, 25741868
SCV000821755	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002530642	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Apr 30, 2021)	germline	curation	PubMed (11) [See all records that cite these PMIDs] 21285249, 21618343, 24136930, 27488870, 30426508, 31312277, 22310028, 30322717, 29052111, 25959805, 25099575 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, curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.

Kluska A, Balabas A, Piatkowska M, Czarny K, Paczkowska K, Nowakowska D, Mikula M, Ostrowski J.

BMC Med Genomics. 2017 Mar 9;10(1):14. doi: 10.1186/s12920-017-0251-8.

PubMed [citation]

PMID:: 28279176
PMCID:: PMC5345197

Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.

Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP.

Science. 2009 Apr 10;324(5924):217. doi: 10.1126/science.1171202. Epub 2009 Mar 5.

PubMed [citation]

PMID:: 19264984
PMCID:: PMC2684332

See all PubMed Citations (21)

Details of each submission

From Ambry Genetics, SCV000172718.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The c.172_175delTTGT (p.Q60Rfs*7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 to 175, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in pancreatic, breast, and ovarian cancer patients, including multiple individuals with family histories significant for PALB2-related cancers (Jones, 2009; Casadei, 2011; Prokofyeva, 2012; Janatova, 2013; Cybulski, 2015; Kluska, 2017; Myszka, 2018). It was also seen in a patient with medulloblastoma (Waszak, 2018). Based on the available evidence, this alteration 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

From Color Diagnostics, LLC DBA Color Health, SCV000685897.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant deletes 4 nucleotides in exon 3 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with breast and/or ovarian cancer (PMID: 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 26283626, 27616075, 28724667, 29052111), 2 individuals affected with pancreatic cancer (PMID: 19264984, 27038244) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in a breast cancer case-control study in 40/12529 cases and 10/4702 unaffected individuals (OR = 4.02, 95% CI 1.6 to 16.2) and a breast cancer case-control meta-analysis in 24/60466 cases and 9/53461 unaffected individuals (OR = 2.358, 95%CI 1.096 to 5.074) (PMID: 25959805, 33471991; Leiden Open Variation Database DB-ID PALB2_010002). This variant has been identified in 12/282872 chromosomes 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

From GeneKor MSA, SCV000821755.2

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

Description

This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of a premature translation stop signal 7 amino acid residues later p.(Gln60Argfs*7). This is expected to result in an absent or disrupted protein product. Truncating mutation in PALB2 gene are known to be pathogenic. The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126623).

#	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 Sema4, Sema4, SCV002530642.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (11)

#	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 20, 2024

ClinVar

Relating variation to medicine