chr16-23635306-G-A

Position:

• chr16-23635306-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000261584.9(PALB2):​c.1240C>T​(p.Arg414Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R414R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23635306-G-A is Pathogenic according to our data. Variant chr16-23635306-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 128117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635306-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1240C>T	p.Arg414Ter	stop_gained	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1240C>T	p.Arg414Ter	stop_gained	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00000798 AC: 2 AN: 250782 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

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: 0.0000460 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:8

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	Genetics and Molecular Pathology, SA Pathology	Apr 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 18, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 23, 2021	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Arg414*) 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 (rs180177100, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 21165770, 21285249, 21618343, 22692731, 24136930, 24448499). ClinVar contains an entry for this variant (Variation ID: 128117). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21285249, 23935836, 21207249, 25099575, 25525159, 24136930, 23935381, 24870022, 26720728, 27067391, 25619955, 27553368, 28024868, 28528518, 26681312, 22692731, 24448499, 25186627, 20412113, 21165770, 21618343, 29945567, 28779002, 29470806, 28724667, 29706558, 30067863, 30322717, 32426482, 32339256, 31589614, 32885271, 34308104, 36003761, 35753512, 30130155, 32853339, 29922827, 32997802, 28888541, 35264596, 31467304, 31619740, 36988593, 35118230, 36978154, 35875117, 36278678, 35685475, 35798629) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2021	This variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals and families with breast cancer or pancreatic ductal adenocarcinoma in the published literature (PMID: 30067863 (2018), 29470806 (2018), 28528518 (2017), 25186627 (2015), 21618343 (2011)). The frequency of this variant in the general population, 0.000029 (1/34586 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2022	The p.R414* pathogenic mutation (also known as c.1240C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in pancreatic, breast, and ovarian cancer patients to date, including multiple individuals with family histories significant for PALB2-related cancers (Slater EP et al. Clin. Genet. 2010 Nov;78:490-4; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Bogdanova N et al. Breast Cancer Res. Treat. 2011 Apr;126:545-50; Hellebrand H et al. Hum. Mutat. 2011 Jun;32:E2176-88; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Kanchi KL et al. Nat. Commun. 2014;5:3156; Antoniou AC et al. N. Engl. J. Med. 2014 Oct;371(17):1651-2; Tung N et al. Cancer. 2015 Jan;121:25-33; Pinto P et al. Breast Cancer Res.Treat. 2016 Sep;159:245-56; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). 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	Mar 29, 2023	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 21165770, 21285249, 21618343, 24136930, 25099575, 25186627, 26681312, 27553368, 29470806, 30128536, 33471991), pancreatic cancer (PMID: 20412113, 27449771, 30067863), and ovarian cancer (PMID: 24448499). In a breast cancer case-control study, PALB2 p.Arg414* was detected in 22/64,780 cases and 3/49,825 unaffected controls (OR 5.89, 95%CI 1.76-19.74, p = 0.004) (PMID: 31467304). This variant has been identified in 2/250782 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2021	Variant summary: PALB2 c.1240C>T (p.Arg414X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 7.9e-06 in 252702 control chromosomes. c.1240C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bogdanova_2011, Casadei_2011, Susswein_2015, Norquist_2016, Sun_2017). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

PALB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The PALB2 c.1240C>T variant is predicted to result in premature protein termination (p.Arg414*). This variant has been reported in multiple individuals with pancreatic or breast or ovarian cancer (see for example: Slater et al. 2010. PubMed ID: 20412113; Bogdanova et al. 2010. PubMed ID: 21165770; Casadei et al. 2011. PubMed ID: 21285249; Kanchi et al. 2014. PubMed ID: 24448499). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Multiple independent submitters in the ClinVar database interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128117/). Nonsense variants in PALB2 are expected to be pathogenic. In summary, this variant is interpreted as pathogenic. -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Immunology and Genetics Kaiserslautern

Jul 31, 2024

ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Arg414X variant was identified in 9 of 5690 proband chromosomes (frequency: 0.0016) from individuals or families with breast and or ovarian cancer negative for BRCA1 and BRCA2 genes mutations and familial pancreatic cancer (Hellebrand 2011 PMID:21618343, Bogdanova 2011 PMID:21165770, Casadei 2011 PMID:21285249, Slater 2010 PMID:20412113, Janatova 2013 PMID:24136930, Antoniou 2014 PMID:25099575). The variant was also identified in the following databases: dbSNP (ID: rs180177100) as “With Pathogenic allele”, ClinVar (6x classified as pathogenic by GeneDx, Invitae, Ambry Genetics, Counsyl, Quest Diagnostics, Fulgent Genetics), Clinvitae (3x as pathogenic by ClinVar and Invitae), LOVD 3.0 (9x, reported as "affects function") and Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 2 of 245860 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 1 of 33574 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 111392 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg414X variant leads to a premature stop codon at position 414 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast, ovarian and pancreatic cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Dec 06, 2023

The PALB2 c.1240C>T (p.Arg414Ter) variant has been reported in over 10 individuals with breast, ovarian, and pancreatic cancer (Antoniou AC et al., PMID: 25099575; Blanco A et al., PMID: 23935836; Bogdanova N et al., PMID: 21165770; Casadei S et al., PMID: 21285249; Catucci I et al., PMID: 22692731; Hellebrand H et al., PMID: 21618343; Janatova M et al., PMID: 24136930; Kanchi KL et al., PMID: 24448499; Schneider R et al., PMID: 21207249). This nonsense variant generates a premature stop codon that is predicted to result in nonsense mediated decay in a gene for which loss of function is a known mechanism of disease. This variant is only observed on 2/250,782 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a pathogenic variant in by 21 submitters (ClinVar Variation ID: 128117). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.83
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177100; hg19: chr16-23646627; COSMIC: COSV55164397; COSMIC: COSV55164397;