VCV000126711.55 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

33 submissions

32 submitters

13 conditions

Reviewed by expert panel

Pathogenic

Apr 2023 by ClinGen Heredi… FDA Recognized Database

for Familial cancer of breast

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 126711 Accession: VCV000126711.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p12.2 16: 23621362 (GRCh38) [ NCBI UCSC ] 16: 23632683 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 19, 2014	Nov 24, 2024	Apr 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.3113G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Trp1038Ter	nonsense
NC_000016.10:g.23621362C>T
NC_000016.9:g.23632683C>T
NG_007406.1:g.24996G>A
LRG_308:g.24996G>A
LRG_308t1:c.3113G>A	LRG_308p1:p.Trp1038Ter

... more HGVS ... less HGVS

Protein change

W1038*

Other names

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

Canonical SPDI

NC_000016.10:23621361:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

ClinGen: CA251004 OMIM: 610355.0013 dbSNP: rs180177132 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PALB2		-	-	GRCh38 GRCh37	5921	5963

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial cancer of breast	Pathogenic (9)	reviewed by expert panel	Apr 5, 2023	RCV000114591.34
Hereditary cancer-predisposing syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 17, 2024	RCV000116096.23
Breast cancer, susceptibility to	risk factor (1)	no assertion criteria provided	Feb 28, 2013	RCV000144703.5
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jul 23, 2024	RCV000212822.19
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	May 8, 2017	RCV000588093.2
Familial cancer of breast Hereditary cancer-predisposing syndrome	Pathogenic (1)	no assertion criteria provided	Sep 1, 2019	RCV001171469.4
Fanconi anemia complementation group N Malignant tumor of breast Pancreatic cancer, susceptibility to, 3	not provided (1)	no classification provided	-	RCV001535480.3
Breast and/or ovarian cancer	Pathogenic (1)	criteria provided, single submitter	Sep 13, 2022	RCV003492443.1
PALB2-related disorder	Pathogenic (2)	criteria provided, single submitter	Sep 19, 2018	RCV004528792.2
NICE approved PARP inhibitor treatment	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2024	RCV004577322.1
Inherited breast cancer and ovarian cancer	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 12, 2024	RCV004584191.2
Inherited ovarian cancer (without breast cancer)	Pathogenic (1)	criteria provided, single submitter	May 3, 2024	RCV004584192.1
Breast-ovarian cancer, familial, susceptibility to, 5	Pathogenic (1)	criteria provided, single submitter	Nov 13, 2023	RCV003389455.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 05, 2023)	reviewed by expert panel (ClinGen HBOP VCEP ACMG Specifications PALB2 V1.0.0) Method: curation	Familial cancer of breast (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV003915565.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/213dcc73-14c2-426c-a6e0-46d72f288c00 Comment: The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as … (more) The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting). (less)
Pathogenic (May 08, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699583.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (6) PubMed: 24206657‚ 25099575‚ 21182766‚ 23448497‚ 26534844‚ 21285249
Pathogenic (Apr 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840027.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: This c.3113G>A (p.Trp1038) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, … (more) This c.3113G>A (p.Trp1038) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, 23471749]. The cumulative risk for carrier of this variant was estimated as 91% by age 70 with a median age of onset of 42 years old reported in an Australian population [PMID 23471749]. This c.3113G>A is located in exon 10 of the PALB2 gene at the exon/intron junction with intron 10. Transcripts analysis showed that this variant not only produces a stop codon at amino acid position 1038 but also produces two additional PALB2 transcripts including an alternative splicing and a complete deletion of exon 10, all three leading to a loss of function of the protein [PMID 23471749]. The c.3113G>A (p.Trp1038*) variant has been observed in two Europeans and one African individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/16-23632683-C-T). It is thus interpreted as a pathogenic variant. (less)
Pathogenic (Sep 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	PALB2-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914711.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 25225577‚ 17200668‚ 21182766‚ 23448497‚ 21285249 Comment: The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of … (more) The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the c.3113G>A (p.Trp1038Ter) variant has been identified in a heterozygous state in at least 21 probands from 13 unrelated families (Rahman et al. 2007; Southey et al. 2010; Teo et al. 2013; Hartley et al. 2014). Affected individuals were found to have a variety of cancers including breast, ovarian, and pancreatic. The p.Trp1038Ter variant was absent from 1724 healthy control subjects and is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Experimental studies on RNA isolated from patient derived lymphoblastoid cell lines have shown that the p.Trp1038Ter variant caused altered splicing (Casadei et al. 2011; Teo et al. 2013). Although this variant has not been reported in any probands with Fanconi anemia, it is known that PALB2 heterozygous variants can also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the evidence from the literature, this variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jan 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	Academic Department of Medical Genetics, University of Cambridge Accession: SCV000992220.1 First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 Comment: Identified as part of research study of individuals with multiple primary tumours referred for genetic assessment	Comment: 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. Observation 1: Clinical Features: Cutaneous melanoma (present) , Breast carcinoma (present) Observation 2: Clinical Features: Anal canal squamous cell carcinoma (present) , Breast carcinoma (present) Observation 3: Clinical Features: Cutaneous melanoma (present) , Breast carcinoma (present) Observation 4: Clinical Features: Malignant tumor of prostate (present)
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002583786.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: PVS1, PS4 Secondary finding: yes
Pathogenic (Oct 26, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000183829.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (13) PubMed: 17200668‚ 21285249‚ 21409391‚ 23448497‚ 23471749‚ 25099575‚ 25225577‚ 25356972‚ 25575445‚ 26283626‚ 28864920‚ 29431189‚ 31843900 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202029.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266105.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: melanoma (present) Age: 40-49 years
Likely pathogenic (Jun 01, 2015)	criteria provided, single submitter (Thompson et al. (Breast Cancer Res. 2015)) Method: case-control	Familial cancer of breast Cases recruited through familial (more...) Affected status: no, yes Allele origin: germline	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Accession: SCV000267971.1 First in ClinVar: May 11, 2016 Last updated: May 11, 2016	Publications: PubMed (1) PubMed: 26283626 Observation 1: Number of individuals with the variant: 7 Sex: female Geographic origin: Australia Observation 2: Number of individuals with the variant: 1 Sex: female Geographic origin: Australia
Pathogenic (Mar 06, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225072.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (5) PubMed: 17200668‚ 21285249‚ 21409391‚ 23448497‚ 23471749 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PALB2 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Jan 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069665.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3113G>A, located in the consensus splice site of the exon. Functional studies have demonstrated … (more) DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3113G>A, located in the consensus splice site of the exon. Functional studies have demonstrated that this sequence change affects normal splicing and creates different PALB2 transcripts in lymphoblastoid cells derived from individuals with breast cancer, including one with complete skipping of exon 10 (deletion of 117 bp), another with an alternative splice site within exon 10 (out-of-frame deletion of 31 bp), and one which results in an immediate stop at amino acid position 1038 (p.Trp1038) (PMID: 21285249, 23448497). The p.Trp1038 change has been reported in individuals and families with breast cancer, with evidence of co-segregation with disease (PMID: 17200668, 21182766, 21285249, 23471749). This sequence change has been observed in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs180177132). These collective evidences suggest that this sequence change is pathogenic. (less)
Pathogenic (Mar 31, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019609.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004101687.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: A known pathogenic mutation was detected in the PALB2 gene (c.3113G>A).This sequence change creates a premature translational stop signal (p.Trp1038) in the PALB2 gene. It … (more) A known pathogenic mutation was detected in the PALB2 gene (c.3113G>A).This sequence change creates a premature translational stop signal (p.Trp1038) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) . It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Published functional studies demonstrate a damaging effect, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (PMID: 21285249, 23448497). For these reasons, this variant has been classified as Pathogenic. (less) Age: 50-59 years Sex: female
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV004228120.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024
Pathogenic (Sep 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239562.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jan 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292142.5 First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 100849‚ 17200668‚ 21182766‚ 21285249‚ 22241545‚ 23448497‚ 23471749‚ 25225577‚ 25356972‚ 26315354‚ 26534844‚ 28864920‚ 31843900‚ 33471991 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166660.15 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 17200668‚ 21182766‚ 21285249‚ 23471749 Comment: This sequence change creates a premature translational stop signal (p.Trp1038) in the PALB2 gene. RNA analysis indicates that this premature translational stop signal induces altered … (more) This sequence change creates a premature translational stop signal (p.Trp1038) in the PALB2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200668, 21182766, 21285249, 23471749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 03, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited ovarian cancer (without breast cancer) Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005068345.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024	Comment: PVS1,PS4
Pathogenic (May 14, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited breast cancer and ovarian cancer Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005068369.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024	Comment: PVS1,PS4
Pathogenic (Jul 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414342.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (14) PubMed: 17200668‚ 21182766‚ 21285249‚ 21409391‚ 23448497‚ 23471749‚ 26283626‚ 26681312‚ 27595995‚ 28158555‚ 28779002‚ 29431189‚ 30322717‚ 31757951 Comment: PM5_supporting, PS4, PVS1 Number of individuals with the variant: 1
Pathogenic (Feb 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502281.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (31) PubMed: 17200668‚ 32081490‚ 31757951‚ 30322717‚ 21285249‚ 32853339‚ 28779002‚ 28864920‚ 29625052‚ 29431189‚ 26689913‚ 32832836‚ 25575445‚ 32338768‚ 31090900‚ 28158555‚ 31263054‚ 27433846‚ 27595995‚ 26681312‚ 32426482‚ 23448497‚ 23471749‚ 26283626‚ 32581362‚ 29909963‚ 21409391‚ 30665703‚ 25525159‚ 29961768‚ 31447099 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Mar 18, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488411.2 First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022	Publications: PubMed (9) PubMed: 21285249‚ 21182766‚ 25099575‚ 24415441‚ 26283626‚ 26315354‚ 21409391‚ 23471749‚ 25575445
Pathogenic (Sep 30, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601775.4 First in ClinVar: Sep 28, 2017 Last updated: Dec 31, 2022	Publications: PubMed (6) PubMed: 23471749‚ 21285249‚ 30665703‚ 22241545‚ 25099575‚ 26534844 Comment: This nonsense variant causes the premature termination of PALB2 protein synthesis. In the published literature, the variant has been reported in one healthy individual, in … (more) This nonsense variant causes the premature termination of PALB2 protein synthesis. In the published literature, the variant has been reported in one healthy individual, in a control group, and in individuals affected with breast or prostate cancer (PMIDs: 30665703 (2019), 27433846 (2016), 26283626 (2015), 25225577 (2014), and 21182766 (2010)). Additionally, splicing studies have shown that this variant produces three alternate transcripts which either result in premature termination of protein synthesis or deletion of exon 10 (PMIDs: 23471749 (2013) and 21285249 (2011)). Based on this information, this variant is classified as pathogenic. (less)
Pathogenic (Feb 11, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000150005.17 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: Observed in multiple individuals with a personal and/or family history of breast cancer and is considered a pathogenic founder variant in the British population (Rahman … (more) Observed in multiple individuals with a personal and/or family history of breast cancer and is considered a pathogenic founder variant in the British population (Rahman 2007, Southey 2010, Wong 2011, Teo 2013, Hartley 2014, Southey 2016, Winship 2016); Published functional studies demonstrate a damaging effect: reduced RAD51 foci formation, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (Pauty 2017, Boonen 2019); This variant is associated with the following publications: (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) (less)
Pathogenic (Apr 30, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	NICE approved PARP inhibitor treatment Affected status: yes Allele origin: germline	Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service Additional submitter: Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005061418.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024	Comment: PVS1,PS4
Pathogenic (Nov 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inherited breast cancer and ovarian cancer Affected status: yes Allele origin: germline	NHS Central & South Genomic Laboratory Hub Accession: SCV005395909.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
Pathogenic (Nov 06, 2014)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000207350.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Publications: PubMed (3) PubMed: 21182766‚ 21285249‚ 23448497
risk factor (Feb 28, 2013)	no assertion criteria provided Method: literature only	BREAST CANCER, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000190693.2 First in ClinVar: Oct 27, 2014 Last updated: Apr 22, 2019	Publications: PubMed (2) PubMed: 17200668‚ 23448497 Comment on evidence: In probands from 2 families with breast cancer (114480), Rahman et al. (2007) identified a 3113G-A transition in the PALB2 gene that resulted in a … (more) In probands from 2 families with breast cancer (114480), Rahman et al. (2007) identified a 3113G-A transition in the PALB2 gene that resulted in a trp1038-to-ter (W1038) amino acid substitution. One proband had been diagnosed at the age of 43 years and had 3 relatives with breast cancer; the other proband had been diagnosed at the age of 49 years and had 4 affected relatives. In 8 of 747 multiplex breast cancer families from Australia and New Zealand, Teo et al. (2013) identified segregation of the c.3113G-A transition in the PALB2 gene. The median age of diagnosis in those carrying this mutation was 48.5 years, with a range of 32 to 79 years. Teo et al. (2013) identified 2 alternative transcripts in RT-PCR assays of the 3113G-A mutation. One involved the deletion of exon 10 (117 bp; r.2997_3113del, Gly1000_Gly1038del), and the other a 31-bp deletion in exon 10 (r.3083_3113del, Gly1028fsTer3). (less)
Pathogenic (Sep 01, 2019)	no assertion criteria provided Method: research	Familial cancer of breast Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	King Laboratory, University of Washington Accession: SCV001251380.1 First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020 Comment: Transcript analysis by cBROCA	Publications: PubMed (1) PubMed: 31843900
Pathogenic (Aug 30, 2024)	no assertion criteria provided Method: clinical testing	PALB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360544.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PALB2 c.3113G>A variant is predicted to result in premature protein termination (p.Trp1038). This variant has been reported in multiple individuals with a personal and/or … (more) The PALB2 c.3113G>A variant is predicted to result in premature protein termination (p.Trp1038). This variant has been reported in multiple individuals with a personal and/or family history of breast cancer (Rahman et al. 2007. PubMed ID: 17200668; Southey et al. 2010. PubMed ID: 21182766; Teo et al. 2013. PubMed ID: 23448497; Teo et al. 2013. PubMed ID: 23471749; Hartley et al. 2014. PubMed ID: 25225577). Functional studies showed that this variant alters splicing and results in three different mRNA transcripts (Casadei et al. 2011. PubMed ID: 21285249). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/126711/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Sep 30, 2019)	no assertion criteria provided Method: curation	not provided Affected status: no Allele origin: germline	Leiden Open Variation Database Accession: SCV001193348.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (15) PubMed: 17200668‚ 18302019‚ 19264984‚ 21182766‚ 21285249‚ 21409391‚ 22241545‚ 23448497‚ 23471749‚ 23787919‚ 24206657‚ 24415441‚ 25099575‚ 25225577‚ 25356972 Comment: Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: James Whitworth, kConFab - Heather Thorne, Marc Tischkowitz.
not provided (-)	no classification provided Method: phenotyping only	Malignant tumor of breast Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749413.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Method: Sanger Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-13 Testing laboratory interpretation: Pathogenic
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Comment:

The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting).

Comment:

This c.3113G>A (p.Trp1038*) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, 23471749]. The cumulative risk for carrier of this variant was estimated as 91% by age 70 with a median age of onset of 42 years old reported in an Australian population [PMID 23471749]. This c.3113G>A is located in exon 10 of the PALB2 gene at the exon/intron junction with intron 10. Transcripts analysis showed that this variant not only produces a stop codon at amino acid position 1038 but also produces two additional PALB2 transcripts including an alternative splicing and a complete deletion of exon 10, all three leading to a loss of function of the protein [PMID 23471749]. The c.3113G>A (p.Trp1038*) variant has been observed in two Europeans and one African individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/16-23632683-C-T). It is thus interpreted as a pathogenic variant.

Comment:

The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the c.3113G>A (p.Trp1038Ter) variant has been identified in a heterozygous state in at least 21 probands from 13 unrelated families (Rahman et al. 2007; Southey et al. 2010; Teo et al. 2013; Hartley et al. 2014). Affected individuals were found to have a variety of cancers including breast, ovarian, and pancreatic. The p.Trp1038Ter variant was absent from 1724 healthy control subjects and is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Experimental studies on RNA isolated from patient derived lymphoblastoid cell lines have shown that the p.Trp1038Ter variant caused altered splicing (Casadei et al. 2011; Teo et al. 2013). Although this variant has not been reported in any probands with Fanconi anemia, it is known that PALB2 heterozygous variants can also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the evidence from the literature, this variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

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.

Comment:

DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3113G>A, located in the consensus splice site of the exon. Functional studies have demonstrated that this sequence change affects normal splicing and creates different PALB2 transcripts in lymphoblastoid cells derived from individuals with breast cancer, including one with complete skipping of exon 10 (deletion of 117 bp), another with an alternative splice site within exon 10 (out-of-frame deletion of 31 bp), and one which results in an immediate stop at amino acid position 1038 (p.Trp1038*) (PMID: 21285249, 23448497). The p.Trp1038* change has been reported in individuals and families with breast cancer, with evidence of co-segregation with disease (PMID: 17200668, 21182766, 21285249, 23471749). This sequence change has been observed in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs180177132). These collective evidences suggest that this sequence change is pathogenic.

Comment:

A known pathogenic mutation was detected in the PALB2 gene (c.3113G>A).This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) . It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Published functional studies demonstrate a damaging effect, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (PMID: 21285249, 23448497). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Comment:

This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200668, 21182766, 21285249, 23471749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

This nonsense variant causes the premature termination of PALB2 protein synthesis. In the published literature, the variant has been reported in one healthy individual, in a control group, and in individuals affected with breast or prostate cancer (PMIDs: 30665703 (2019), 27433846 (2016), 26283626 (2015), 25225577 (2014), and 21182766 (2010)). Additionally, splicing studies have shown that this variant produces three alternate transcripts which either result in premature termination of protein synthesis or deletion of exon 10 (PMIDs: 23471749 (2013) and 21285249 (2011)). Based on this information, this variant is classified as pathogenic.

Comment:

Observed in multiple individuals with a personal and/or family history of breast cancer and is considered a pathogenic founder variant in the British population (Rahman 2007, Southey 2010, Wong 2011, Teo 2013, Hartley 2014, Southey 2016, Winship 2016); Published functional studies demonstrate a damaging effect: reduced RAD51 foci formation, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (Pauty 2017, Boonen 2019); This variant is associated with the following publications: (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768)

Comment:

The PALB2 c.3113G>A variant is predicted to result in premature protein termination (p.Trp1038*). This variant has been reported in multiple individuals with a personal and/or family history of breast cancer (Rahman et al. 2007. PubMed ID: 17200668; Southey et al. 2010. PubMed ID: 21182766; Teo et al. 2013. PubMed ID: 23448497; Teo et al. 2013. PubMed ID: 23471749; Hartley et al. 2014. PubMed ID: 25225577). Functional studies showed that this variant alters splicing and results in three different mRNA transcripts (Casadei et al. 2011. PubMed ID: 21285249). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/126711/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Defined lifestyle and germline factors predispose Asian populations to gastric cancer.	Suzuki A	Science advances	2020	PMID: 32426482
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.	Abdel-Rahman MH	Ophthalmology	2020	PMID: 32081490
Characterization of splice-altering mutations in inherited predisposition to cancer.	Casadei S	Proceedings of the National Academy of Sciences of the United States of America	2019	PMID: 31843900
Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2.	Boonen RACM	Nature communications	2019	PMID: 31757951
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer.	Petridis C	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2019	PMID: 31263054
Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.	Nones K	Annals of oncology : official journal of the European Society for Medical Oncology	2019	PMID: 31090900
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.	Wright CF	American journal of human genetics	2019	PMID: 30665703
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.	Yurgelun MB	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29961768
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.	Whitworth J	American journal of human genetics	2018	PMID: 29909963
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
Molecular analysis of PALB2-associated breast cancers.	Lee JEA	The Journal of pathology	2018	PMID: 29431189
Discovery of mutations in homologous recombination genes in African-American women with breast cancer.	Ding YC	Familial cancer	2018	PMID: 28864920
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.	Decker B	Journal of medical genetics	2017	PMID: 28779002
Cancer-causing mutations in the tumor suppressor PALB2 reveal a novel cancer mechanism using a hidden nuclear export signal in the WD40 repeat motif.	Pauty J	Nucleic acids research	2017	PMID: 28158555
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.	Southey MC	Journal of medical genetics	2016	PMID: 27595995
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.	Pritchard CC	The New England journal of medicine	2016	PMID: 27433846
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.	Li J	Journal of medical genetics	2016	PMID: 26534844
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.	Ramus SJ	Journal of the National Cancer Institute	2015	PMID: 26315354
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.	Thompson ER	Breast cancer research : BCR	2015	PMID: 26283626
Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.	Nguyen-Dumont T	Breast cancer research and treatment	2015	PMID: 25575445
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.	Zhen DB	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356972
Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada.	Hartley T	Hereditary cancer in clinical practice	2014	PMID: 25225577
Breast-cancer risk in families with mutations in PALB2.	Antoniou AC	The New England journal of medicine	2014	PMID: 25099575
Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer.	Fernandes PH	Cancer	2014	PMID: 24415441
Hi-Plex for high-throughput mutation screening: application to the breast cancer susceptibility gene PALB2.	Nguyen-Dumont T	BMC medical genomics	2013	PMID: 24206657
Tumour morphology predicts PALB2 germline mutation status.	Teo ZL	British journal of cancer	2013	PMID: 23787919
The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia.	Teo ZL	Familial cancer	2013	PMID: 23471749
Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families.	Teo ZL	Breast cancer research : BCR	2013	PMID: 23448497
Rare germline mutations in PALB2 and breast cancer risk: a population-based study.	Tischkowitz M	Human mutation	2012	PMID: 22241545
BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer.	Wong MW	Breast cancer research and treatment	2011	PMID: 21409391
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.	Casadei S	Cancer research	2011	PMID: 21285249
A PALB2 mutation associated with high risk of breast cancer.	Southey MC	Breast cancer research : BCR	2010	PMID: 21182766
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.	Jones S	Science (New York, N.Y.)	2009	PMID: 19264984
Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families.	García MJ	Breast cancer research and treatment	2009	PMID: 18302019
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.	Rahman N	Nature genetics	2007	PMID: 17200668
[Endemic goiter and the physical development of children].	Januszko T	Roczniki Akademii Medycznej im. Juliana Marchlewskiego w Bialymstoku	1977	PMID: 100849
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PALB2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/213dcc73-14c2-426c-a6e0-46d72f288c00	-	-	-	-
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Text-mined citations for rs180177132 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs180177132 ...