NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 17, 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:: RCV000116096.23

Allele description [Variation Report for NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)]

NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)

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.3113G>A (p.Trp1038Ter)

Other names:

PALB2, TRP1038TER (rs180177132); p.W1038*:TGG>TAG; NM_024675.3(PALB2):c.3113G>A; p.Trp1038Ter

HGVS:

NC_000016.10:g.23621362C>T
NG_007406.1:g.24996G>A
NM_024675.4:c.3113G>AMANE SELECT
NP_078951.2:p.Trp1038Ter
NP_078951.2:p.Trp1038Ter
LRG_308t1:c.3113G>A
LRG_308:g.24996G>A
LRG_308p1:p.Trp1038Ter
NC_000016.9:g.23632683C>T
NM_024675.3:c.3113G>A
p.Trp1038*
p.Trp1038Stop
p.W1038*

Protein change:

W1038*; TRP1038TER

Links:

OMIM: 610355.0013; dbSNP: rs180177132

NCBI 1000 Genomes Browser:

rs180177132

Molecular consequence:

NM_024675.4:c.3113G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000183829	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 26, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 17200668, 21285249, 21409391, 23448497, 23471749, 25099575, 25225577, 25356972, 25575445, 26283626, 28864920, 29431189, 31843900 Citation Link,
SCV000266105	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000292142	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 100849, 17200668, 21182766, 21285249, 22241545, 23448497, 23471749, 25225577, 25356972, 26315354, 26534844, 28864920, 31843900, 33471991, 25741868
SCV000992220	Academic Department of Medical Genetics, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004228120	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	5	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer.

Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Avery-Kiejda KA, Talseth-Palmer B, Bowden NA, Scott RJ.

Breast Cancer Res Treat. 2011 Jun;127(3):853-9. doi: 10.1007/s10549-011-1443-0. Epub 2011 Mar 16.

PubMed [citation]

PMID:: 21409391

Breast-cancer risk in families with mutations in PALB2.

Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, et al.

N Engl J Med. 2014 Aug 7;371(6):497-506. doi: 10.1056/NEJMoa1400382.

PubMed [citation]

PMID:: 25099575
PMCID:: PMC4157599

See all PubMed Citations (21)

Details of each submission

From Ambry Genetics, SCV000183829.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The c.3113G>A pathogenic mutation (also known as p.W1038*), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3113. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This change occurs in the last base pair of coding exon 10, and has been shown to generate three aberrant mRNA isoforms: one with complete skipping of exon 10 (deletion of 117 bp), another which uses an alternative splice site within exon 10 (out-of-frame deletion of 31 bp) (Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, this mutation has been identified in multiple early-onset breast cancer probands with significant breast cancer family histories (Hartley T et al. Hered Cancer Clin Pract. 2014;12:19; Teo ZL et al. Fam. Cancer. 2013 Dec;12:587-95; Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Wong MW et al. Breast Cancer Res. Treat. 2011 Jun;127:853-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Ding YC et al. Fam. Cancer. 2018 Apr;17:187-195). This alteration has also been reported in a kindred with at least two family members affected with pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). 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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000266105.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000292142.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This variant causes a nonsense mutation in exon 10 and is also predicted to disrupt splicing at the intron 10 splice donor site in the PALB2 gene. RNA studies have reported that this variant causes splicing defects resulting in an in-frame deletion of exon 10 or exons 9 and 10, impacting the WD40 domain of PALB2, or an out-of-frame transcript due to the use of a cryptic donor site within exon 10 that results in a premature translational stop signal. Normally spliced transcript from the mutant allele has a nonsense mutation due to the coding sequence change (PMID: 21285249, 23448497, 31843900). This variant has been observed in over a dozen individuals affected with early-onset breast cancer with positive history of breast and other cancers (PMID: 17200668, 21182766, 21285249, 22241545, 23471749, 25225577, 28864920; DOI: 10.1016/j.gimo.2023.100849), an individual affected with familial pancreatic cancer (PMID: 25356972), and in two individuals affected with ovarian cancer and two unaffected individuals (PMID: 26315354). This variant has been detected in a breast cancer case-control meta-analysis in 31/60466 cases and 6/53461 unaffected individuals with an estimated odds ratio of 4.57 (95% CI 1.906 to 10.955) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010150). This variant has been shown to segregate with breast cancer in families (PMID: 21182766, 26534844). This variant has been identified in 17/282756 chromosomes in the general population by the Genome Aggregation Database (gnomAD), predominantly in non-Finnish Europeans and also in African-Americans. 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 Academic Department of Medical Genetics, University of Cambridge, SCV000992220.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)
3	not provided	1	not provided	not provided	research	PubMed (1)
4	not provided	1	not provided	not provided	research	PubMed (1)

Description

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV004228120.1

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

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine