rs180177100

Variant names:

• chr16-23635306-G-A
• rs180177100
• NM_024675.4:c.1240C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23635306-G-A
• chr16-23635306-G-C
• chr16-23635306-G-T

Variant summary

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

The NM_024675.4(PALB2):​c.1240C>T​(p.Arg414*) 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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28
• 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 rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1240C>T	p.Arg414*	stop_gained	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1240C>T	p.Arg414*	stop_gained	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

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:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:8

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate -

Jul 18, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PM2_SUP -

Jul 26, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:7

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2019

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. -

Mar 05, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:4

Oct 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1240C>T (p.R414*) alteration, located in exon 4 (coding exon 4) of the PALB2 gene, consists of a C to T substitution at nucleotide position 1240. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 414. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/250782) total alleles studied. The highest observed frequency was 0.003% (1/34586) of Latino alleles. This variant has been reported heterozygous in multiple individuals with features consistent with PALB2-related cancer predisposition (Slater, 2010; Casadei, 2011; Bogdanova, 2011; Hellebrand, 2011; Janatova, 2013; Kanchi, 2014; Antoniou, 2014; Tung, 2015; Pinto, 2016; Brand, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM2_SUP, PM5_SUP -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:2

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PS4 -

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Sep 28, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PALB2-related disorder Pathogenic:1

Feb 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

Jul 31, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 06, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;