rs180177132

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong

The NM_024675.4(PALB2):c.3113G>A(p.Trp1038Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000208 in 1,602,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PALB2
NM_024675.4 stop_gained, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:25O:2

Conservation

PhyloP100: 4.74

Variant links:

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-23621362-C-T is Pathogenic according to our data. Variant chr16-23621362-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 126711.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-23621362-C-T is described in Lovd as [Pathogenic]. Variant chr16-23621362-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3113G>A	p.Trp1038Ter	stop_gained, splice_region_variant	10/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3113G>A	p.Trp1038Ter	stop_gained, splice_region_variant	10/13	1	NM_024675.4	P1
	ENST00000561764.1 linkuse as main transcript	n.420-2538C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251360

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000228

AC:

331

AN:

1450660

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

149

AN XY:

722506

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000293

Gnomad4 OTH exome

AF:

0.0000666

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000819

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 11, 2022	PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Likely pathogenic, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 03, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2018	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Sep 30, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: James Whitworth, kConFab - Heather Thorne, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 15, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 09, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 01, 2023	- -

PALB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 19, 2018

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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 13, 2022

- -

Breast-ovarian cancer, familial, susceptibility to, 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Nov 13, 2023

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. -

Hereditary cancer-predisposing syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2017

- -

Breast cancer, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 28, 2013

- -

Malignant tumor of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

Vest4

0.90

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.74

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over