rs180177100

chr16-23635306-G-Achr16-23635306-G-Cchr16-23635306-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_024675.4(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
NM_024675.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 6.80

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1240C>T	p.Arg414Ter	stop_gained	4/13	ENST00000261584.9

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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:

AN:

250782

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135674

show subpopulations

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:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727182

show subpopulations

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:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2016	- -
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	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	Genetics and Molecular Pathology, SA Pathology	Apr 29, 2020	- -
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	Invitae	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. -
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 -

not provided

Pathogenic:6

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	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
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	- -
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	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. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

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. -
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. -

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	- -

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

- -

PALB2-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

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. -

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 â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

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

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